Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

IAP-targeted therapies for cancer

Abstract

DNA damage, chromosomal abnormalities, oncogene activation, viral infection, substrate detachment and hypoxia can all trigger apoptosis in normal cells. However, cancer cells acquire mutations that allow them to survive these threats that are part and parcel of the transformation process or that may affect the growth and dissemination of the tumor. Eventually, cancer cells accumulate further mutations that make them resistant to apoptosis mediated by standard cytotoxic chemotherapy or radiotherapy. The inhibitor of apoptosis (IAP) family members, defined by the presence of a baculovirus IAP repeat (BIR) protein domain, are key regulators of cytokinesis, apoptosis and signal transduction. Specific IAPs regulate either cell division, caspase activity or survival pathways mediated through binding to their BIR domains, and/or through their ubiquitin-ligase RING domain activity. These protein–protein interactions and post-translational modifications are the subject of intense investigations that shed light on how these proteins contribute to oncogenesis and resistance to therapy. In the past several years, we have seen multiple approaches of IAP antagonism enter the clinic, and the rewards of such strategies are about to reap benefit. Significantly, small molecule pan-IAP antagonists that mimic an endogenous inhibitor of the IAPs, called Smac, have demonstrated an unexpected ability to sensitize cancer cells to tumor necrosis factor-α and to promote autocrine or paracrine production of this cytokine by the tumor cell and possibly, other cells too. This review will focus on these and other developmental therapeutics that target the IAPs in cancer.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4

References

  • Adida C, Crotty PL, McGrath J, Berrebi D, Diebold J, Altieri D . (1998). Developmentally regulated expression of the novel cancer anti-apoptosis gene survivin in human and mouse differentiation. Am J Pathol 152: 43–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Adrain C, Creagh EM, Martin SJ . (2001). Apoptosis-associated release of Smac/DIABLO from mitochondria requires active caspases and is blocked by Bcl-2. EMBO J 20: 6627–6636.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Altieri DC . (2001). The molecular basis and potential role of survivin in cancer diagnosis and therapy. Trends Mol Med 7: 542–547.

    CAS  PubMed  Google Scholar 

  • Altieri DC . (2008). Survivin, cancer networks and pathway-directed drug discovery. Nat Rev Cancer 8: 61–70.

    CAS  PubMed  Google Scholar 

  • Amantana A, London CA, Iversen PL, Devi GR . (2004). X-linked inhibitor of apoptosis protein inhibition induces apoptosis and enhances chemotherapy sensitivity in human prostate cancer cells. Mol Cancer Ther 3: 699–707.

    CAS  PubMed  Google Scholar 

  • Ambrosini G, Adida C, Altieri D . (1997). A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 3: 917–921.

    CAS  PubMed  Google Scholar 

  • Ambrosini G, Adida C, Sirugo G, Altieri DC . (1998). Induction of apoptosis and inhibition of cell proliferation by survivin gene targeting. J Biol Chem 273: 11177–11182.

    CAS  PubMed  Google Scholar 

  • Annunziata CM, Davis RE, Demchenko Y, Bellamy W, Gabrea A, Zhan F et al. (2007). Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell 12: 115–130.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ansell SM, Arendt BK, Grote DM, Jelinek DF, Novak AJ, Wellik LE et al. (2004). Inhibition of survivin expression suppresses the growth of aggressive non-Hodgkin's lymphoma. Leukemia 18: 616–623.

    CAS  PubMed  Google Scholar 

  • Arnt CR, Chiorean MV, Heldebrant MP, Gores GJ, Kaufmann SH . (2002). Synthetic Smac/DIABLO peptides enhance the effects of chemotherapeutic agents by binding XIAP and cIAP1 in situ. J Biol Chem 277: 44236–44243.

    CAS  PubMed  Google Scholar 

  • Arora V, Cheung HH, Plenchette S, Micali OC, Liston P, Korneluk RG . (2007). Degradation of survivin by the X-linked inhibitor of apoptosis (XIAP)-XAF1 complex. J Biol Chem 282: 26202–26209.

    CAS  PubMed  Google Scholar 

  • Ashhab Y, Alian A, Polliack A, Panet A, Ben Yehuda D . (2001). Two splicing variants of a new inhibitor of apoptosis gene with different biological properties and tissue distribution pattern. FEBS Lett 495: 56–60.

    CAS  PubMed  Google Scholar 

  • Baens M, Fevery S, Sagaert X, Noels H, Hagens S, Broeckx V et al. (2006). Selective expansion of marginal zone B cells in Eμ-API2-MALT1 mice is linked to enhanced IkappaB kinase gamma polyubiquitination. Cancer Res 66: 5270–5277.

    CAS  PubMed  Google Scholar 

  • Baens M, Maes B, Steyls A, Geboes K, Marynen P, De Wolf-Peeters C . (2000). The product of the t(11;18), an API2-MLT fusion, marks nearly half of gastric MALT type lymphomas without large cell proliferation. Am J Pathol 156: 1433–1439.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bauvois B, Dauzonne D . (2006). Aminopeptidase-N/CD13 (EC 3.4.11.2) inhibitors: chemistry, biological evaluations, and therapeutic prospects. Med Res Rev 26: 88–130.

    CAS  PubMed  Google Scholar 

  • Bertrand MJ, Milutinovic S, Dickson KM, Ho WC, Boudreault A, Durkin J et al. (2008). cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol Cell 30: 689–700.

    CAS  PubMed  Google Scholar 

  • Bockbrader KM, Tan M, Sun Y . (2005). A small molecule Smac-mimic compound induces apoptosis and sensitizes TRAIL- and etoposide-induced apoptosis in breast cancer cells. Oncogene 24: 7381–7388.

    CAS  PubMed  Google Scholar 

  • Brennan DJ, Rexhepaj E, O’Brien SL, McSherry E, O’Connor DP, Fagan A et al. (2008). Altered cytoplasmic-to-nuclear ratio of survivin is a prognostic indicator in breast cancer. Clin Cancer Res 14: 2681–2689.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bria E, Visca P, Novelli F, Casini B, Diodoro MG, Perrone-Donnorso R et al. (2008). Nuclear and cytoplasmic cellular distribution of survivin as survival predictor in resected non-small-cell lung cancer. Eur J Surg Oncol 34: 593–598.

    CAS  PubMed  Google Scholar 

  • Burri L, Strahm Y, Hawkins CJ, Gentle IE, Puryer MA, Verhagen A et al. (2005). Mature DIABLO/Smac is produced by the IMP protease complex on the mitochondrial inner membrane. Mol Biol Cell 16: 2926–2933.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Buzzai M, Jones RG, Amaravadi RK, Lum JJ, DeBerardinis RJ, Zhao F et al. (2007). Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res 67: 6745–6752.

    CAS  PubMed  Google Scholar 

  • Cao C, Mu Y, Hallahan DE, Lu B . (2004). XIAP and survivin as therapeutic targets for radiation sensitization in preclinical models of lung cancer. Oncogene 23: 7047–7052, 9448.

    CAS  PubMed  Google Scholar 

  • Carter BZ, Gronda M, Wang Z, Welsh K, Pinilla C, Andreeff M et al. (2005). Small-molecule XIAP inhibitors derepress downstream effector caspases and induce apoptosis of acute myeloid leukemia cells. Blood 105: 4043–4050.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chai J, Du C, Wu JW, Kyin S, Wang X, Shi Y . (2000). Structural and biochemical basis of apoptotic activation by Smac/DIABLO. Nature 406: 855–862.

    CAS  PubMed  Google Scholar 

  • Chang CC, Heller JD, Kuo J, Huang RC . (2004). Tetra-O-methyl nordihydroguaiaretic acid induces growth arrest and cellular apoptosis by inhibiting Cdc2 and survivin expression. Proc Natl Acad Sci USA 101: 13239–13244.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chantalat L, Skoufias DA, Kleman JP, Jung B, Dideberg O, Margolis RL . (2000). Crystal structure of human survivin reveals a bow tie-shaped dimer with two unusual alpha-helical extensions. Mol Cell 6: 183–189.

    CAS  PubMed  Google Scholar 

  • Chastagner P, Israel A, Brou C . (2006). Itch/AIP4 mediates Deltex degradation through the formation of K29-linked polyubiquitin chains. EMBO Rep 7: 1147–1153.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen J, Nikolovska-Coleska Z, Wang G, Qiu S, Wang S . (2006). Design, synthesis, and characterization of new embelin derivatives as potent inhibitors of X-linked inhibitor of apoptosis protein. Bioorg Med Chem Lett 16: 5805–5808.

    CAS  PubMed  Google Scholar 

  • Chen Z, Naito M, Hori S, Mashiima T, Yamori T, Tsuruo T . (1999). A human IAP-family gene, apollon, expressed in human brain cancer cells. Biochem Biophys Res Commun 264: 847–854.

    CAS  PubMed  Google Scholar 

  • Cheung HH, LaCasse EC, Korneluk RG . (2006a). X-linked inhibitor of apoptosis antagonism: strategies in cancer treatment. Clin Cancer Res 12: 3238–3242.

    CAS  PubMed  Google Scholar 

  • Cheung HH, Kelly LN, Liston P, Korneluk RG . (2006b). Involvement of caspase-2 and caspase-9 in endoplasmic reticulum stress-induced apoptosis: a role for the IAPs. Exp Cell Res 312: 2347–2357.

    CAS  PubMed  Google Scholar 

  • Cheung HH, Plenchette S, Kern CJ, Mahoney DJ, Korneluk RG . (2008). The RING domain of cIAP1 mediates the degradation of RING-bearing inhibitor of apoptosis proteins by distinct pathways. Mol Biol Cell 19: 2729–2740.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chu ZL, McKinsey TA, Liu L, Gentry JJ, Malim MH, Ballard DW . (1997). Suppression of tumor necrosis factor-induced cell death by inhibitor of apoptosis c-IAP2 is under NF-kappaB control. Proc Natl Acad Sci USA 94: 10057–10062.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chung SK, Lee MG, Ryu BK, Lee JH, Han J, Byun DS et al. (2007). Frequent alteration of XAF1 in human colorectal cancers: implication for tumor cell resistance to apoptotic stresses. Gastroenterology 132: 2459–2477.

    CAS  PubMed  Google Scholar 

  • Cillessen SA, Reed JC, Welsh K, Pinilla C, Houghten R, Hooijberg E et al. (2008). Small-molecule XIAP antagonist restores caspase-9 mediated apoptosis in XIAP-positive diffuse large B-cell lymphoma cells. Blood 111: 369–375.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Clem RJ, Sheu TT, Richter BW, He WW, Thornberry NA, Duckett CS et al. (2001). c-IAP1 is cleaved by caspases to produce a proapoptotic C-terminal fragment. J Biol Chem 276: 7602–7608.

    CAS  PubMed  Google Scholar 

  • Conte D, Holcik M, Lefebvre CA, LaCasse E, Picketts DJ, Wright KE et al. (2006). Inhibitor of apoptosis protein cIAP2 is essential for lipopolysaccharide-induced macrophage survival. Mol Cell Biol 26: 699–708.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Conway EM, Pollefeyt S, Cornelissen J, DeBaere I, Steiner-Mosonyi M, Ong K et al. (2000). Three differentially expressed survivin cDNA variants encode proteins with distinct antiapoptotic functions. Blood 95: 1435–1442.

    CAS  PubMed  Google Scholar 

  • Conze DB, Albert L, Ferrick DA, Goeddel DV, Yeh WC, Mak T et al. (2005). Posttranscriptional downregulation of c-IAP2 by the ubiquitin protein ligase c-IAP1 in vivo. Mol Cell Biol 25: 3348–3356.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Coornaert B, Baens M, Heyninck K, Bekaert T, Haegman M, Staal J et al. (2008). T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappaB inhibitor A20. Nat Immunol 9: 263–271.

    CAS  PubMed  Google Scholar 

  • Creagh EM, Murphy BM, Duriez PJ, Duckett CS, Martin SJ . (2004). Smac/Diablo antagonizes ubiquitin ligase activity of inhibitor of apoptosis proteins. J Biol Chem 279: 26906–26914.

    CAS  PubMed  Google Scholar 

  • Crnkovic-Mertens I, Semzow J, Hoppe-Seyler F, Butz K . (2006). Isoform-specific silencing of the Livin gene by RNA interference defines Livin beta as key mediator of apoptosis inhibition in HeLa cells. J Mol Med 84: 232–240.

    CAS  PubMed  Google Scholar 

  • Cummings J, Ranson M, LaCasse E, Ganganagari JR, St-Jean M, Jayson G et al. (2006). Method validation and preliminary qualification of pharmacodynamic biomarkers employed to evaluate the clinical efficacy of an antisense compound (AEG35156) targeted to the X-linked inhibitor of apoptosis protein XIAP. Br J Cancer 95: 42–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dai Z, Zhu WG, Morrison CD, Brena RM, Smiraglia DJ, Raval A et al. (2003). A comprehensive search for DNA amplification in lung cancer identifies inhibitors of apoptosis cIAP1 and cIAP2 as candidate oncogenes. Hum Mol Genet 12: 791–801.

    CAS  PubMed  Google Scholar 

  • Dan HC, Sun M, Kaneko S, Feldman RI, Nicosia SV, Wang HG et al. (2004). Akt phosphorylation and stabilization of X-linked inhibitor of apoptosis protein (XIAP). J Biol Chem 279: 5405–5412.

    CAS  PubMed  Google Scholar 

  • Danson S, Dean E, Dive C, Ranson M . (2007). IAPs as a target for anticancer therapy. Curr Cancer Drug Targets 7: 785–794.

    CAS  PubMed  Google Scholar 

  • Davoodi J, Lin L, Kelly J, Liston P, MacKenzie AE . (2004). Neuronal apoptosis-inhibitory protein does not interact with Smac and requires ATP to bind caspase-9. J Biol Chem 279: 40622–40628.

    CAS  PubMed  Google Scholar 

  • Dean EJ, Ranson M, Blackhall F, Holt SV, Dive C . (2007). Novel therapeutic targets in lung cancer: inhibitor of apoptosis proteins from laboratory to clinic. Cancer Treat Rev 33: 203–212.

    CAS  PubMed  Google Scholar 

  • Deveraux QL, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula SM et al. (1998). IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J 17: 2215–2223.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Deveraux QL, Takahashi R, Salvesen GS, Reed JC . (1997). X-linked IAP is a direct inhibitor of cell-death proteases. Nature 388: 300–304.

    CAS  PubMed  Google Scholar 

  • Dierlamm J, Baens M, Wlodarska I, Stefanova-Ouzounova M, Hernandez JM, Hossfeld DK et al. (1999). The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue lymphomas. Blood 93: 3601–3609.

    CAS  PubMed  Google Scholar 

  • Dohi T, Okada K, Xia F, Wilford CE, Samuel T, Welsh K et al. (2004). An IAP-IAP complex inhibits apoptosis. J Biol Chem 279: 34087–34090.

    CAS  PubMed  Google Scholar 

  • Dohi T, Xia F, Altieri DC . (2007). Compartmentalized phosphorylation of IAP by protein kinase A regulates cytoprotection. Mol Cell 27: 17–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Du C, Fang M, Li Y, Li L, Wang X . (2000). Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 102: 33–42.

    CAS  PubMed  Google Scholar 

  • Du MQ . (2007). MALT lymphoma: recent advances in aetiology and molecular genetics. J Clin Exp Hematop 47: 31–42.

    PubMed  Google Scholar 

  • Duckett CS, Nava VE, Gedrich RW, Clem RJ, Van Dongen JL, Gilfillan MC et al. (1996). A conserved family of cellular genes related to the baculovirus iap gene and encoding apoptosis inhibitors. EMBO J 15: 2685–2694.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ea CK, Deng L, Xia ZP, Pineda G, Chen ZJ . (2006). Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Mol Cell 22: 245–257.

    CAS  PubMed  Google Scholar 

  • Eckelman BP, Salvesen GS . (2006). The human anti-apoptotic proteins cIAP1 and cIAP2 bind but do not inhibit caspases. J Biol Chem 281: 3254–3260.

    CAS  PubMed  Google Scholar 

  • Eckelman BP, Salvesen GS, Scott FL . (2006). Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family. EMBO Rep 7: 988–994.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ekert PG, Vaux DL . (2005). The mitochondrial death squad: hardened killers or innocent bystanders? Curr Opin Cell Biol 17: 626–630.

    CAS  PubMed  Google Scholar 

  • Engelsma D, Rodriguez JA, Fish A, Giaccone G, Fornerod M . (2007). Homodimerization antagonizes nuclear export of survivin. Traffic 8: 1495–1502.

    CAS  PubMed  Google Scholar 

  • Erl W, Hansson GK, de Martin R, Draude G, Weber KS, Weber C . (1999). Nuclear factor-kappa B regulates induction of apoptosis and inhibitor of apoptosis protein-1 expression in vascular smooth muscle cells. Circ Res 84: 668–677.

    CAS  PubMed  Google Scholar 

  • Evan GI, Vousden KH . (2001). Proliferation, cell cycle and apoptosis in cancer. Nature 411: 342–348.

    CAS  PubMed  Google Scholar 

  • Ferreira CG, van der Valk P, Span SW, Jonker JM, Postmus PE, Kruyt FA et al. (2001a). Assessment of IAP (inhibitor of apoptosis) proteins as predictors of response to chemotherapy in advanced non-small-cell lung cancer patients. Ann Oncol 12: 799–805.

    CAS  PubMed  Google Scholar 

  • Ferreira CG, van der Valk P, Span SW, Ludwig I, Smit EF, Kruyt FA . (2001b). Expression of X-linked inhibitor of apoptosis as a novel prognostic marker in radically resected non-small cell lung cancer patients. Clin Cancer Res 7: 2468–2474.

    CAS  PubMed  Google Scholar 

  • Fong WG, Liston P, Rajcan-Separovic E, St Jean M, Craig C, Korneluk RG . (2000). Expression and genetic analysis of XIAP-associated factor 1 (XAF1) in cancer cell lines. Genomics 70: 113–122.

    CAS  PubMed  Google Scholar 

  • Fortugno P, Beltrami E, Plescia J, Fontana J, Pradhan D, Marchisio PC et al. (2003). Regulation of survivin function by Hsp90. Proc Natl Acad Sci USA 100: 13791–13796.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fu J, Jin Y, Arend LJ . (2003). Smac3, a novel Smac/DIABLO splicing variant, attenuates the stability and apoptosis-inhibiting activity of X-linked inhibitor of apoptosis protein. J Biol Chem 278: 52660–52672.

    CAS  PubMed  Google Scholar 

  • Fukuda S, Pelus LM . (2006). Survivin, a cancer target with an emerging role in normal adult tissues. Mol Cancer Ther 5: 1087–1098.

    CAS  PubMed  Google Scholar 

  • Fulda S, Wick W, Weller M, Debatin KM . (2002). Smac agonists sensitize for Apo2 L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat Med 8: 808–815.

    CAS  PubMed  Google Scholar 

  • Gaither A, Porter D, Yao Y, Borawski J, Yang G, Donovan J et al. (2007). A Smac mimetic rescue screen reveals roles for inhibitor of apoptosis proteins in tumor necrosis factor-alpha signaling. Cancer Res 67: 11493–11498.

    CAS  PubMed  Google Scholar 

  • Galderisi U, Cascino A, Giordano A . (1999). Antisense oligonucleotides as therapeutic agents. J Cell Phys 181: 251–257.

    CAS  Google Scholar 

  • Galvan V, Kurakin AV, Bredesen DE . (2004). Interaction of checkpoint kinase 1 and the X-linked inhibitor of apoptosis during mitosis. FEBS Lett 558: 57–62.

    CAS  PubMed  Google Scholar 

  • Gleave M, Miyake H, Zangemeister-Wittke U, Jansen B . (2002). Antisense therapy: current status in prostate cancer and other malignancies. Cancer Metastasis Rev 21: 79–92.

    CAS  PubMed  Google Scholar 

  • Goncalves RB, Sanches D, Souza TL, Silva JL, Oliveira AC . (2008). The proapoptotic protein Smac/DIABLO dimer has the highest stability as measured by pressure and urea denaturation. Biochemistry 47: 3832–3841.

    CAS  PubMed  Google Scholar 

  • Grossman D, Kim PJ, Schechner JS, Altieri DC . (2001). Inhibition of melanoma tumor growth in vivo by survivin targeting. Proc Natl Acad Sci USA 98: 635–640.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Guan TJ, Qin FJ, Du JH, Geng L, Zhang YY, Li M . (2007). AICAR inhibits proliferation and induced S-phase arrest, and promotes apoptosis in CaSki cells. Acta Pharmacol Sin 28: 1984–1990.

    CAS  PubMed  Google Scholar 

  • Guo F, Nimmanapalli R, Paranawithana S, Wittman S, Griffin D, Bali P et al. (2002). Ectopic overexpression of second mitochondria-derived activator of caspases (Smac/DIABLO) or cotreatment with N-terminus of Smac/DIABLO peptide potentiates epothilone B derivative-(BMS 247550) and Apo-2 L/TRAIL-induced apoptosis. Blood 99: 3419–3426.

    CAS  PubMed  Google Scholar 

  • Hanahan D, Weinberg RA . (2000). The hallmarks of cancer. Cell 100: 57–70.

    CAS  PubMed  Google Scholar 

  • Hao Y, Sekine K, Kawabata A, Nakamura H, Ishioka T, Ohata H et al. (2004). Apollon ubiquitinates SMAC and caspase-9, and has an essential cytoprotection function. Nat Cell Biol 6: 849–860.

    CAS  PubMed  Google Scholar 

  • Hauser HP, Bardroff M, Pyrowolakis G, Jentsch S . (1998). A giant ubiquitin-conjugating enzyme related to IAP apoptosis inhibitors. J Cell Biol 141: 1415–1422.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hegde R, Srinivasula SM, Datta P, Madesh M, Wassell R, Zhang Z et al. (2003). The polypeptide chain-releasing factor GSPT1/eRF3 is proteolytically processed into an IAP-binding protein. J Biol Chem 278: 38699–38706.

    CAS  PubMed  Google Scholar 

  • Hegde R, Srinivasula SM, Zhang Z, Wassell R, Mukattash R, Cilenti L et al. (2002). Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein–caspase interaction. J Biol Chem 277: 432–438.

    CAS  PubMed  Google Scholar 

  • Hess CJ, Berkhof J, Denkers F, Ossenkoppele GJ, Schouten JP, Oudejans JJ et al. (2007). Activated intrinsic apoptosis pathway is a key related prognostic parameter in acute myeloid leukemia. J Clin Oncol 25: 1209–1215.

    CAS  PubMed  Google Scholar 

  • Hinds MG, Norton RS, Vaux DL, Day CL . (1999). Solution structure of a baculoviral inhibitor of apoptosis (IAP) repeat. Nat Struct Biol 6: 648–651.

    CAS  PubMed  Google Scholar 

  • Hochstrasser M . (2006). Lingering mysteries of ubiquitin-chain assembly. Cell 124: 27–34.

    PubMed  Google Scholar 

  • Hong SY, Yoon WH, Park JH, Kang SG, Ahn JH, Lee TH . (2000). Involvement of two NF-kappa B binding elements in tumor necrosis factor alpha -, CD40-, and Epstein–Barr virus latent membrane protein 1-mediated induction of the cellular inhibitor of apoptosis protein 2 gene. J Biol Chem 275: 18022–18028.

    CAS  PubMed  Google Scholar 

  • Hosokawa Y . (2005). Anti-apoptotic action of API2-MALT1 fusion protein involved in t(11;18)(q21;q21) MALT lymphoma. Apoptosis 10: 25–34.

    CAS  PubMed  Google Scholar 

  • Hu H, Shikama Y, Matsuoka I, Kimura J . (2008). Terminally differentiated neutrophils predominantly express Survivin-2 alpha, a dominant-negative isoform of survivin. J Leukoc Biol 83: 393–400.

    CAS  PubMed  Google Scholar 

  • Hu S, Alcivar A, Qu L, Tang J, Yang X . (2006a). CIAP2 inhibits anigen receptor signaling by targeting Bcl10 for degredation. Cell Cycle 5: 1438–1442.

    CAS  PubMed  Google Scholar 

  • Hu S, Du MQ, Park SM, Alcivar A, Qu L, Gupta S et al. (2006b). cIAP2 is a ubiquitin protein ligase for BCL10 and is dysregulated in mucosa-associated lymphoid tissue lymphomas. J Clin Invest 116: 174–181.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hu Y, Cherton-Horvat G, Dragowska V, Baird S, Korneluk RG, Durkin JP et al. (2003). Antisense oligonucleotides targeting XIAP induce apoptosis and enhance chemotherapeutic activity against human lung cancer cells in vitro and in vivo. Clin Cancer Res 9: 2826–2836.

    CAS  PubMed  Google Scholar 

  • Huang RC, Chang CC, Mold D . (2006). Survivin-dependent and -independent pathways and the induction of cancer cell death by tetra-O-methyl nordihydroguaiaretic acid. Semin Oncol 33: 479–485.

    CAS  PubMed  Google Scholar 

  • Huang Y, Rich RL, Myszka DG, Wu H . (2003). Requirement of both the second and third BIR domains for the relief of X-linked inhibitor of apoptosis protein (XIAP)-mediated caspase inhibition by Smac. J Biol Chem 278: 49517–49522.

    CAS  PubMed  Google Scholar 

  • Hunter AM, LaCasse EC, Korneluk RG . (2007). The inhibitors of apoptosis (IAPs) as cancer targets. Apoptosis 12: 1543–1568.

    CAS  PubMed  Google Scholar 

  • Hunter T . (2007). The age of crosstalk: phosphorylation, ubiquitination, and beyond. Mol Cell 28: 730–738.

    CAS  PubMed  Google Scholar 

  • Imoto I, Yang ZQ, Pimkhaokham A, Tsuda H, Shimada Y, Imamura M et al. (2001). Identification of cIAP1 as a candidate target gene within an amplicon at 11q22 in esophageal squamous cell carcinomas. Cancer Res 61: 6629–6634.

    CAS  PubMed  Google Scholar 

  • Isakovic A, Harhaji L, Stevanovic D, Markovic Z, Sumarac-Dumanovic M, Starcevic V et al. (2007). Dual antiglioma action of metformin: cell cycle arrest and mitochondria-dependent apoptosis. Cell Mol Life Sci 64: 1290–1302.

    CAS  PubMed  Google Scholar 

  • Islam A, Kageyama H, Hashizume K, Kaneko Y, Nakagawara A . (2000). Role of survivin, whose gene is mapped to 17q25, in human neuroblastoma and identification of a novel dominant-negative isoform, survivin-beta/2B. Med Ped Oncol 35: 550–553.

    CAS  Google Scholar 

  • Jansen B, Zangemeister-Wittke U . (2002). Antisense therapy for cancer––the time of truth. The Lancet 3: 672–683.

    CAS  PubMed  Google Scholar 

  • Jeyaprakash AA, Klein UR, Lindner D, Ebert J, Nigg EA, Conti E . (2007). Structure of a Survivin-Borealin-INCENP core complex reveals how chromosomal passengers travel together. Cell 131: 271–285.

    CAS  PubMed  Google Scholar 

  • Jiang X, Wilford C, Duensing S, Munger K, Jones G, Jones D . (2001). Participation of Survivin in mitotic and apoptotic activities of normal and tumor-derived cells. J Cell Biochem 83: 342–354.

    CAS  PubMed  Google Scholar 

  • Jin C, Reed JC . (2002). Yeast and apoptosis. Nat Rev Mol Cell Biol 3: 453–459.

    CAS  PubMed  Google Scholar 

  • Kandasamy K, Srinivasula SM, Alnemri ES, Thompson CB, Korsemeyer SJ, Bryant JL et al. (2003). Involvement of proapoptotic molecules Bax and Bak in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced mitochondrial disruption and apoptosis: differential regulation of cytochrome c and Smac/DIABLO release. Cancer Res 63: 1712–1721.

    CAS  PubMed  Google Scholar 

  • Kanneganti TD, Lamkanfi M, Nunez G . (2007). Intracellular NOD-like receptors in host defense and disease. Immunity 27: 549–559.

    CAS  PubMed  Google Scholar 

  • Kappler M, Rot S, Taubert H, Greither T, Bartel F, Dellas K et al. (2007). The effects of knockdown of wild-type survivin, survivin-2B or survivin-delta3 on the radiosensitization in a soft tissue sarcoma cells in vitro under different oxygen conditions. Cancer Gene Ther 14: 994–1001.

    CAS  PubMed  Google Scholar 

  • Karikari CA, Roy I, Tryggestad E, Feldmann G, Pinilla C, Welsh K et al. (2007). Targeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis protein. Mol Cancer Ther 6: 957–966.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kasof GM, Gomes BC . (2001). Livin, a novel inhibitor of apoptosis protein family member. J Biol Chem 276: 3238–3246.

    CAS  PubMed  Google Scholar 

  • Kaur S, Wang F, Venkatraman M, Arsura M . (2005). X-linked inhibitor of apoptosis (XIAP) inhibits c-Jun N-terminal kinase 1 (JNK1) activation by transforming growth factor beta1 (TGF-beta1) through ubiquitin-mediated proteosomal degradation of the TGF-beta1-activated kinase 1 (TAK1). J Biol Chem 280: 38599–38608.

    CAS  PubMed  Google Scholar 

  • Keats JJ, Fonseca R, Chesi M, Schop R, Baker A, Chng WJ et al. (2007). Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell 12: 131–144.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kipp RA, Case MA, Wist AD, Cresson CM, Carrell M, Griner E et al. (2002). Molecular targeting of inhibitor of apoptosis proteins based on small molecule mimics of natural binding partners. Biochemistry 41: 7344–7349.

    CAS  PubMed  Google Scholar 

  • Kleinberg L, Florenes VA, Silins I, Haug K, Trope CG, Nesland JM et al. (2007). Nuclear expression of survivin is associated with improved survival in metastatic ovarian carcinoma. Cancer 109: 228–238.

    CAS  PubMed  Google Scholar 

  • Knauer SK, Bier C, Schlag P, Fritzmann J, Dietmaier W, Rodel F et al. (2007). The survivin isoform survivin-3B is cytoprotective and can function as a chromosomal passenger complex protein. Cell Cycle 6: 1502–1509.

    CAS  PubMed  Google Scholar 

  • Kobayashi K, Hatano M, Otaki M, Ogasawara T, Tokuhisa T . (1999). Expression of a murine homologue of the inhibitor of apoptosis protein is related to cell proliferation. Proc Natl Acad Sci USA 96: 1457–1462.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Koh HJ, Brandauer J, Goodyear LJ . (2008). LKB1 and AMPK and the regulation of skeletal muscle metabolism. Curr Opin Clin Nutr Metab Care 11: 227–232.

    CAS  PubMed  PubMed Central  Google Scholar 

  • LaCasse EC, Baird S, Korneluk RG, MacKenzie AE . (1998). The inhibitors of apoptosis (IAPs) and their emerging role in cancer. Oncogene 17: 3247–3259.

    PubMed  Google Scholar 

  • LaCasse EC, Kandimalla ER, Winocour P, Sullivan T, Agrawal S, Gillard JW et al. (2005). Therapeutic oligonucleotides: transcriptional and translational strategies for silencing gene expression. Ann NY Acad Sci 1058: 215–234.

    CAS  PubMed  Google Scholar 

  • Lagace M, Xuan JY, Young SS, McRoberts C, Maier J, Rajcan-Separovic E et al. (2001). Genomic organization of the X-linked inhibitor of apoptosis and identification of a novel testis-specific transcript. Genomics 77: 181–188.

    CAS  PubMed  Google Scholar 

  • Leaman DW, Chawla-Sarkar M, Vyas K, Reheman M, Tamai K, Toji S et al. (2002). Identification of X-linked inhibitor of apoptosis-associated factor-1 as an interferon-stimulated gene that augments TRAIL Apo2 L-induced apoptosis. J Biol Chem 277: 28504–28511.

    CAS  PubMed  Google Scholar 

  • Lee TH, Shank J, Cusson N, Kelliher MA . (2004). The kinase activity of Rip1 is not required for tumor necrosis factor-alpha-induced IkappaB kinase or p38 MAP kinase activation or for the ubiquitination of Rip1 by Traf2. J Biol Chem 279: 33185–33191.

    CAS  PubMed  Google Scholar 

  • Li F . (2005). Role of survivin and its splice variants in tumorigenesis. Br J Cancer 92: 212–216.

    CAS  PubMed  Google Scholar 

  • Li F, Ackermann EJ, Bennett CF, Rothermel AL, Plescia J, Tognin S et al. (1999). Pleiotropic cell-division defects and apoptosis induced by interference with survivin function. Nat Cell Biol 1: 461–466.

    CAS  PubMed  Google Scholar 

  • Li J, Feng Q, Kim JM, Schneiderman D, Liston P, Li M et al. (2001). Human ovarian cancer and cisplatin resistance: possible role of inhibitor of apoptosis proteins. Endocrinology 142: 370–380.

    CAS  PubMed  Google Scholar 

  • Li L, Thomas RM, Suzuki H, De Brabander JK, Wang X, Harran PG . (2004). A small molecule Smac mimic potentiates TRAIL- and TNFalpha-mediated cell death. Science 305: 1471–1474.

    CAS  PubMed  Google Scholar 

  • Li X, Yang Y, Ashwell JD . (2002). TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2. Nature 416: 345–347.

    PubMed  Google Scholar 

  • Lima RT, Martins LM, Guimaraes JE, Sambade C, Vasconcelos MH . (2004). Specific downregulation of bcl-2 and xIAP by RNAi enhances the effects of chemotherapeutic agents in MCF-7 human breast cancer cells. Cancer Gene Ther 11: 309–316.

    CAS  PubMed  Google Scholar 

  • Liston P, Fong WG, Kelly NL, Toji S, Miyazaki T, Conte D et al. (2001). Identification of XAF1 as an antagonist of XIAP anti-caspase activity. Nat Cell Biol 3: 128–133.

    CAS  PubMed  Google Scholar 

  • Liston P, Fong WG, Korneluk RG . (2003). The inhibitors of apoptosis: there is more to life than Bcl2. Oncogene 22: 8568–8580.

    CAS  PubMed  Google Scholar 

  • Liston P, Roy N, Tamai K, Lefebvre C, Baird S, Cherton-Horvat G et al. (1996). Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes. Nature 379: 349–353.

    CAS  PubMed  Google Scholar 

  • Liu S, Tsang BK, Cheung AN, Xue WC, Cheng DK, Ng TY . (2001). Anti-apoptotic proteins, apoptotic and proliferative parameters and their prognostic significance in cervical carcinoma. Eur J Cancer 37: 1104–1110.

    CAS  PubMed  Google Scholar 

  • Liu Z, Sun C, Olejniczak ET, Meadows RP, Betz SF, Oost T et al. (2000). Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain. Nature 408: 1004–1008.

    CAS  PubMed  Google Scholar 

  • Lu M, Lin SC, Huang Y, Kang YJ, Rich R, Lo YC et al. (2007). XIAP induces NF-kappaB activation via the BIR1/TAB1 interaction and BIR1 dimerization. Mol Cell 26: 689–702.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lucas PC, Kuffa P, Gu S, Kohrt D, Kim DS, Siu K et al. (2007). Dual role for the API2 moiety in API2-MALT1-dependent NF-kappaB activation: heterotypic oligomerization and TRAF2 recruitment. Oncogene 26: 5643–5654.

    CAS  PubMed  Google Scholar 

  • Madesh M, Antonsson B, Srinivasula SM, Alnemri ES, Hajnóckzy G . (2002). Rapid kinetics of tBid-induced cytochrome c and Smac/DIABLO release and mitochondrial depolarization. J Biol Chem 277: 5651–5659.

    CAS  PubMed  Google Scholar 

  • Mahoney DJ, Cheung HH, Lejmi Mrad R, Plenchette S, Simard C, Enwere E et al. (2008). Both cIAP1 and cIAP2 regulate TNFα-mediated NF-κB activation. Proc Natl Acad Sci USA 105: 11778–11783.

    CAS  Google Scholar 

  • Mao HL, Liu PS, Zheng JF, Zhang PH, Zhou LG, Xin G et al. (2007). Transfection of Smac/DIABLO sensitizes drug-resistant tumor cells to TRAIL or paclitaxel-induced apoptosis in vitro. Pharmacol Res 56: 483–492.

    CAS  PubMed  Google Scholar 

  • Mariathasan S, Monack DM . (2007). Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation. Nat Rev Immunol 7: 31–40.

    CAS  PubMed  Google Scholar 

  • Martin SJ . (2001). Dealing the CARDs between life and death. Trends Cell Biol 11: 188–189.

    CAS  PubMed  Google Scholar 

  • Martins LM, Iaccarino I, Tenev T, Gschmeissner S, Totty NF, Lemoine NR et al. (2002). The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a reaper-like motif. J Biol Chem 277: 439–444.

    CAS  PubMed  Google Scholar 

  • McManus DC, Lefebvre CA, Cherton-Horvat G, St-Jean M, Kandimalla ER, Agrawal S et al. (2004). Loss of XIAP protein expression by RNAi and antisense approaches sensitizes cancer cells to functionally diverse chemotherapeutics. Oncogene 23: 8105–8117.

    CAS  PubMed  Google Scholar 

  • Meli M, Pennati M, Curto M, Daidone MG, Plescia J, Toba S et al. (2006). Small-molecule targeting of heat shock protein 90 chaperone function: rational identification of a new anticancer lead. J Med Chem 49: 7721–7730.

    CAS  PubMed  Google Scholar 

  • Mesri M, Wall NR, Li J, Kim RW, Altieri D . (2001). Cancer gene therapy using a survivin mutant adenovirus. J Clin Invest 108: 981–990.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Micali OC, Cheung HH, Plenchette S, Hurley SL, Liston P, LaCasse EC et al. (2007). Silencing of the XAF1 gene by promoter hypermethylation in cancer cells and reactivation to TRAIL-sensitization by IFN-beta. BMC Cancer 7: 52.

    PubMed  PubMed Central  Google Scholar 

  • Mizutani Y, Nakanishi H, Li YN, Matsubara H, Yamamoto K, Sato N et al. (2007). Overexpression of XIAP expression in renal cell carcinoma predicts a worse prognosis. Int J Oncol 30: 919–925.

    CAS  PubMed  Google Scholar 

  • Mola G, Vela E, Fernandez-Figueras MT, Isamat M, Munoz-Marmol AM . (2007). Exonization of Alu-generated splice variants in the survivin gene of human and non-human primates. J Mol Biol 366: 1055–1063.

    CAS  PubMed  Google Scholar 

  • Mosley JD, Keri RA . (2006). Splice variants of mIAP1 have an enhanced ability to inhibit apoptosis. Biochem Biophys Res Commun 348: 1174–1183.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nachmias B, Mizrahi S, Elmalech M, Lazar I, Ashhab Y, Gazit R et al. (2007). Manipulation of NK cytotoxicity by the IAP family member Livin. Eur J Immunol 37: 3467–3476.

    CAS  PubMed  Google Scholar 

  • Nakahara T, Takeuchi M, Kinoyama I, Minematsu T, Shirasuna K, Matsuhisa A et al. (2007). YM155, a novel small-molecule survivin suppressant, induces regression of established human hormone-refractory prostate tumor xenografts. Cancer Res 67: 8014–8021.

    CAS  PubMed  Google Scholar 

  • Ng CP, Bonavida B . (2002). X-linked inhibitor of apoptosis (XIAP) blocks Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis of prostate cancer cells in the presence of mitochondrial activation: sensitization by overexpression of second mitochondria-derived activator of caspase/direct IAP-binding protein with low pl (Smac/DIABLO). Mol Cancer Ther 1: 1051–1058.

    CAS  PubMed  Google Scholar 

  • Nikolovska-Coleska Z, Xu L, Hu Z, Tomita Y, Li P, Roller PP et al. (2004). Discovery of embelin as a cell-permeable, small-molecular weight inhibitor of XIAP through structure-based computational screening of a traditional herbal medicine three-dimensional structure database. J Med Chem 47: 2430–2440.

    CAS  PubMed  Google Scholar 

  • Noels H, van Loo G, Hagens S, Broeckx V, Beyaert R, Marynen P et al. (2007). A novel TRAF6 binding site in MALT1 defines distinct mechanisms of NF-kappaB activation by API2·MALT1 fusions. J Biol Chem 282: 10180–10189.

    CAS  PubMed  Google Scholar 

  • Noton EA, Colnaghi R, Tate S, Starck C, Carvalho A, Ko Ferrigno P et al. (2006). Molecular analysis of survivin isoforms: evidence that alternatively spliced variants do not play a role in mitosis. J Biol Chem 281: 1286–1295.

    CAS  PubMed  Google Scholar 

  • O’Connor DS, Grossman D, Plescia J, Li F, Zhang H, Villa A et al. (2000). Regulation of apoptosis at cell division by p34cdc2 phosphorylation of survivin. Proc Natl Acad Sci USA 97: 13103–13107.

    PubMed  PubMed Central  Google Scholar 

  • O’Donnell MA, Legarda-Addison D, Skountzos P, Yeh WC, Ting AT . (2007). Ubiquitination of RIP1 regulates an NF-kappaB-independent cell-death switch in TNF signaling. Curr Biol 17: 418–424.

    PubMed  PubMed Central  Google Scholar 

  • Obiol-Pardo C, Granadino-Roldan JM, Rubio-Martinez J . (2008). Protein–protein recognition as a first step towards the inhibition of XIAP and Survivin anti-apoptotic proteins. J Mol Recognit 21: 190–204.

    CAS  PubMed  Google Scholar 

  • Olie RA, Simoes-Wust AP, Baumann B, Leech SH, Fabbro D, Stahel RA et al. (2000). A novel antisense oligonucleotide targeting survivin expression induces apoptosis and sensitizes lung cancer cells to chemotherapy. Cancer Res 60: 2805–2809.

    CAS  PubMed  Google Scholar 

  • Oost TK, Sun C, Armstrong RC, Al-Assaad AS, Betz SF, Deckwerth TL et al. (2004). Discovery of potent antagonists of the antiapoptotic protein XIAP for the treatment of cancer. J Med Chem 47: 4417–4426.

    CAS  PubMed  Google Scholar 

  • Pannone G, Bufo P, Serpico R, Rubini C, Zamparese R, Corsi F et al. (2007). Survivin phosphorylation and M-phase promoting factor in oral carcinogenesis. Histol Histopathol 22: 1241–1249.

    CAS  PubMed  Google Scholar 

  • Park CM, Sun C, Olejniczak ET, Wilson AE, Meadows RP, Betz SF et al. (2005). Non-peptidic small molecule inhibitors of XIAP. Bioorg Med Chem Lett 15: 771–775.

    CAS  PubMed  Google Scholar 

  • Petersen SL, Wang L, Yalcin-Chin A, Li L, Peyton M, Minna J et al. (2007). Autocrine TNFalpha signaling renders human cancer cells susceptible to Smac-mimetic-induced apoptosis. Cancer Cell 12: 445–456.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pinho MB, Costas F, Sellos J, Dienstmann R, Andrade PB, Herchenhorn D et al. (2008). XAF1 mRNA expression improves progression-free and overall survival for patients with advanced bladder cancer treated with neoadjuvant chemotherapy. Urol Oncol; e-pub June 16.

  • Piras F, Murtas D, Minerba L, Ugalde J, Floris C, Maxia C et al. (2007). Nuclear survivin is associated with disease recurrence and poor survival in patients with cutaneous malignant melanoma. Histopathology 50: 835–842.

    CAS  PubMed  Google Scholar 

  • Plenchette S, Cathelin S, Rebe C, Launay S, Ladoire S, Sordet O et al. (2004). Translocation of the inhibitor of apoptosis protein c-IAP1 from the nucleus to the Golgi in hematopoietic cells undergoing differentiation: a nuclear export signal-mediated event. Blood 104: 2035–2043.

    CAS  PubMed  Google Scholar 

  • Plenchette S, Cheung HH, Fong WG, LaCasse EC, Korneluk RG . (2007). The role of XAF1 in cancer. Curr Opin Investig Drugs 8: 469–476.

    CAS  PubMed  Google Scholar 

  • Plescia J, Salz W, Xia F, Pennati M, Zaffaroni N, Daidone MG et al. (2005). Rational design of shepherdin, a novel anticancer agent. Cancer Cell 7: 457–468.

    CAS  PubMed  Google Scholar 

  • Pohl C, Jentsch S . (2008). Final stages of cytokinesis and midbody ring formation are controlled by BRUCE. Cell 132: 832–845.

    CAS  PubMed  Google Scholar 

  • Qi R, Gu J, Zhang Z, Yang K, Li B, Fan J et al. (2006). Potent antitumor efficacy of XAF1 delivered by conditionally replicative adenovirus vector via caspase-independent apoptosis. Cancer Gene Ther 14: 82–90.

    PubMed  Google Scholar 

  • Qiu XB, Goldberg AL . (2005). The membrane-associated inhibitor of apoptosis protein, BRUCE/Apollon, antagonizes both the precursor and mature forms of Smac and caspase-9. J Biol Chem 280: 174–182.

    CAS  PubMed  Google Scholar 

  • Ramp U, Krieg T, Caliskan E, Mahotka C, Ebert T, Willers R et al. (2004). XIAP expression is an independent prognostic marker in clear-cell renal carcinomas. Hum Pathol 35: 1022–1028.

    CAS  PubMed  Google Scholar 

  • Rebeaud F, Hailfinger S, Posevitz-Fejfar A, Tapernoux M, Moser R, Rueda D et al. (2008). The proteolytic activity of the paracaspase MALT1 is key in T cell activation. Nat Immunol 9: 272–281.

    CAS  PubMed  Google Scholar 

  • Remstein ED, James CD, Kurtin PJ . (2000). Incidence and subtype specificity of API2-MALT1 fusion translocations in extranodal, nodal, and splenic marginal zone lymphomas. Am J Pathol 156: 1183–1188.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Reu FJ, Bae SI, Cherkassky L, Leaman DW, Lindner D, Beaulieu N et al. (2006). Overcoming resistance to interferon-induced apoptosis of renal carcinoma and melanoma cells by DNA demethylation. J Clin Oncol 24: 3771–3779.

    CAS  PubMed  Google Scholar 

  • Rhee I, Bachman KE, Park BH, Jair KW, Yen RW, Schuebel KE et al. (2002). DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature 416: 552–556.

    CAS  PubMed  Google Scholar 

  • Richter BW, Mir SS, Eiben LJ, Lewis J, Reffrey SB, Frattini A et al. (2001). Molecular cloning of ILP-2, a novel member of the inhibitor of apoptosis protein family. Mol Cell Biol 21: 4292–4301.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rigaud S, Fondaneche MC, Lambert N, Pasquier B, Mateo V, Soulas P et al. (2006). XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature 444: 110–114.

    CAS  PubMed  Google Scholar 

  • Roberts DL, Merrison W, MacFarlane M, Cohen GM . (2001). The inhibitor of apoptosis protein-binding domain of Smac is not essential for its proapoptotic activity. J Cell Biol 153: 221–227.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Robertson AJ, Croce J, Carbonneau S, Voronina E, Miranda E, McClay DR et al. (2006). The genomic underpinnings of apoptosis in Strongylocentrotus purpuratus. Dev Biol 300: 321–334.

    CAS  PubMed  Google Scholar 

  • Rothe M, Pan MG, Henzel WJ, Ayres TM, Goeddel DV . (1995). The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Cell 83: 1243–1252.

    CAS  PubMed  Google Scholar 

  • Roy N, Mahadevan MS, McLean M, Shutler G, Yaraghi Z, Farahani R et al. (1995). The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell 80: 167–178.

    CAS  PubMed  Google Scholar 

  • Ruchaud S, Carmena M, Earnshaw WC . (2007). Chromosomal passengers: conducting cell division. Nat Rev Mol Cell Biol 8: 798–812.

    CAS  PubMed  Google Scholar 

  • Sagaert X, Theys T, De Wolf-Peeters C, Marynen P, Baens M . (2006). Splenic marginal zone lymphoma-like features in API2-MALT1 transgenic mice that are exposed to antigenic stimulation. Haematologica 91: 1693–1696.

    CAS  PubMed  Google Scholar 

  • Samuel T, Welsh K, Lober T, Togo SH, Zapata JM, Reed JC . (2006). Distinct BIR domains of cIAP1 mediate binding to and ubiquitination of tumor necrosis factor receptor-associated factor 2 and second mitochondrial activator of caspases. J Biol Chem 281: 1080–1090.

    CAS  PubMed  Google Scholar 

  • Sanna MG, da Silva Correia J, Ducrey O, Lee J, Nomoto K, Schrantz N et al. (2002a). IAP suppression of apoptosis involves distinct mechanisms: the TAK1/JNK1 signaling cascade and caspase inhibition. Mol Cell Biol 22: 1754–1766.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sanna MG, da Silva Correia J, Luo Y, Chuang B, Paulson LM, Nguyen B et al. (2002b). ILPIP, a novel anti-apoptotic protein that enhances XIAP-mediated activation of JNK1 and protection against apoptosis. J Biol Chem 277: 30454–30462.

    CAS  PubMed  Google Scholar 

  • Sanna MG, Duckett CS, Richter BW, Thompson CB, Ulevitch RJ . (1998). Selective activation of JNK1 is necessary for the anti-apoptotic activity of hILP. Proc Natl Acad Sci USA 95: 6015–6020.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Santoro MM, Samuel T, Mitchell T, Reed JC, Stainier DY . (2007). Birc2 (cIap1) regulates endothelial cell integrity and blood vessel homeostasis. Nat Genet 39: 1397–1402.

    CAS  PubMed  Google Scholar 

  • Sato S, Aoyama H, Miyachi H, Naito M, Hashimoto Y . (2008). Demonstration of direct binding of cIAP1 degradation-promoting bestatin analogs to BIR3 domain: synthesis and application of fluorescent bestatin ester analogs. Bioorg Med Chem Lett 18: 3354–3358.

    CAS  PubMed  Google Scholar 

  • Schimmer AD, Welsh K, Pinilla C, Wang Z, Krajewska M, Bonneau MJ et al. (2004). Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity. Cancer Cell 5: 25–35.

    CAS  PubMed  Google Scholar 

  • Schulze-Luehrmann J, Ghosh S . (2006). Antigen-receptor signaling to nuclear factor kappa B. Immunity 25: 701–715.

    CAS  PubMed  Google Scholar 

  • Seligson DB, Hongo F, Huerta-Yepez S, Mizutani Y, Miki T, Yu H et al. (2007). Expression of X-linked inhibitor of apoptosis protein is a strong predictor of human prostate cancer recurrence. Clin Cancer Res 13: 6056–6063.

    CAS  PubMed  Google Scholar 

  • Shankar SL, Mani S, O’Guin KN, Kandimalla ER, Agrawal S, Shafit-Zagardo B . (2001). Survivin inhibition induces human neural tumor cell death through caspase-independent and -dependent pathways. J Neurochem 79: 426–436.

    CAS  PubMed  Google Scholar 

  • Shim JH, Xiao C, Paschal AE, Bailey ST, Rao P, Hayden MS et al. (2005). TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. Genes Dev 19: 2668–2681.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shin H, Okada K, Wilkinson JC, Solomon KM, Duckett CS, Reed JC et al. (2003). Identification of ubiquitination sites on the X-linked inhibitor of apoptosis protein. Biochem J 373: 965–971.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shin H, Renatus M, Eckelman BP, Nunes VA, Sampaio CA, Salvesen GS . (2005). The BIR domain of IAP-like protein 2 is conformationally unstable: implications for caspase inhibition. Biochem J 385: 1–10.

    CAS  PubMed  Google Scholar 

  • Shu HB, Takeuchi M, Goeddel DV . (1996). The tumor necrosis factor receptor 2 signal transducers TRAF2 and c-IAP1 are components of the tumor necrosis factor receptor 1 signaling complex. Proc Natl Acad Sci USA 93: 13973–13978.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Silke J, Kratina T, Chu D, Ekert PG, Day CL, Pakusch M et al. (2005). Determination of cell survival by RING-mediated regulation of inhibitor of apoptosis (IAP) protein abundance. Proc Natl Acad Sci USA 102: 16182–16187.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Span PN, Tjan-Heijnen VC, Heuvel JJ, de Kok JB, Foekens JA, Sweep FC . (2006). Do the survivin (BIRC5) splice variants modulate or add to the prognostic value of total survivin in breast cancer? Clin Chem 52: 1693–1700.

    CAS  PubMed  Google Scholar 

  • Srinivasula SM, Hegde R, Saleh A, Datta P, Shiozaki E, Chai J et al. (2001). A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis. Nature 410: 112–116.

    CAS  PubMed  Google Scholar 

  • Stamm S, Riethoven JJ, Le Texier V, Gopalakrishnan C, Kumanduri V, Tang Y et al. (2006). ASD: a bioinformatics resource on alternative splicing. Nucleic Acids Res 34: D46–D55.

    CAS  PubMed  Google Scholar 

  • Stauber RH, Mann W, Knauer SK . (2007). Nuclear and cytoplasmic survivin: molecular mechanism, prognostic, and therapeutic potential. Cancer Res 67: 5999–6002.

    CAS  PubMed  Google Scholar 

  • Sun C, Cai M, Gunasekera AH, Meadows RP, Wang H, Chen J et al. (1999). NMR structure and mutagenesis of the inhibitor-of-apoptosis protein XIAP. Nature 401: 818–822.

    CAS  PubMed  Google Scholar 

  • Suzuki Y, Nakabayashi Y, Takahashi R . (2001). Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death. Proc Natl Acad Sci USA 98: 8662–8667.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Swinney DC, Xu YZ, Scarafia LE, Lee I, Mak AY, Gan QF et al. (2002). A small molecule ubiquitination inhibitor blocks NF-kappa B-dependent cytokine expression in cells and rats. J Biol Chem 277: 23573–23581.

    CAS  PubMed  Google Scholar 

  • Swisher SG, Roth JA, Nemunaitis J, Lawrence DD, Kemp BL, Carrasco CH et al. (1999). Adenovirus-mediated p53 gene transfer in advanced non-small-cell lung cancer. J Natl Cancer Inst 91: 763–771.

    CAS  PubMed  Google Scholar 

  • Tamm I, Kornblau SM, Segall H, Krajewski S, Welsh K, Kitada S et al. (2000). Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias. Clin Cancer Res 6: 1796–1803.

    CAS  PubMed  Google Scholar 

  • Ting JP, Willingham SB, Bergstralh DT . (2008). NLRs at the intersection of cell death and immunity. Nat Rev Immunol 8: 372–379.

    CAS  PubMed  Google Scholar 

  • Towler MC, Hardie DG . (2007). AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res 100: 328–341.

    CAS  PubMed  Google Scholar 

  • Tu SP, Jiang XH, Lin MC, Cui JT, Yang Y, Lum CT et al. (2003). Suppression of survivin expression inhibits in vivo tumorigenicity and angiogenesis in gastric cancer. Cancer Res 63: 7724–7732.

    CAS  PubMed  Google Scholar 

  • Uren AG, O’Rourke K, Aravind LA, Pisabarro MT, Seshagiri S, Koonin EV et al. (2000). Identification of paracaspases and metacaspases: two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphoma. Mol Cell 6: 961–967.

    CAS  PubMed  Google Scholar 

  • Uren AG, Pakusch M, Hawkins CJ, Puls KL, Vaux DL . (1996). Cloning and expression of apoptosis inhibitory protein homologs that function to inhibit apoptosis and/or bind tumor necrosis factor receptor-associated factors. Proc Natl Acad Sci USA 93: 4974–4978.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Varambally S, Yu J, Laxman B, Rhodes DR, Mehra R, Tomlins SA et al. (2005). Integrative genomic and proteomic analysis of prostate cancer reveals signatures of metastatic progression. Cancer Cell 8: 393–406.

    CAS  PubMed  Google Scholar 

  • Varfolomeev E, Blankenship JW, Wayson SM, Fedorova AV, Kayagaki N, Garg P et al. (2007). IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. Cell 131: 669–681.

    CAS  PubMed  Google Scholar 

  • Varfolomeev E, Wayson SM, Dixit VM, Fairbrother WJ, Vucic D . (2006). The inhibitor of apoptosis protein fusion c-IAP2.MALT1 stimulates NF-kappaB activation independently of TRAF1 AND TRAF2. J Biol Chem 281: 29022–29029.

    CAS  PubMed  Google Scholar 

  • Vaux DL, Silke J . (2005). IAPs, RINGs and ubiquitylation. Nat Rev Mol Cell Biol 6: 287–297.

    CAS  PubMed  Google Scholar 

  • Vega F, Medeiros LJ . (2001). Marginal-zone B-cell lymphoma of extranodal mucosa-associated lymphoid tissue type: molecular genetics provides new insights into pathogenesis. Adv Anat Pathol 8: 313–326.

    CAS  PubMed  Google Scholar 

  • Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE et al. (2000). Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 102: 43–53.

    CAS  PubMed  Google Scholar 

  • Verhagen AM, Kratina TK, Hawkins CJ, Silke J, Ekert PG, Vaux DL . (2007). Identification of mammalian mitochondrial proteins that interact with IAPs via N-terminal IAP binding motifs. Cell Death Differ 14: 348–357.

    CAS  PubMed  Google Scholar 

  • Verhagen AM, Silke J, Ekert PG, Pakusch M, Kaufmann H, Connolly LM et al. (2002). HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins. J Biol Chem 277: 445–454.

    CAS  PubMed  Google Scholar 

  • Vince JE, Chau D, Callus B, Wong WW, Hawkins CJ, Schneider P et al. (2008). TWEAK-FN14 signaling induces lysosomal degradation of a cIAP1-TRAF2 complex to sensitize tumor cells to TNFalpha. J Cell Biol 184: 171–184.

    Google Scholar 

  • Vince JE, Wong WW, Khan N, Feltham R, Chau D, Ahmed AU et al. (2007). IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis. Cell 131: 682–693.

    CAS  PubMed  Google Scholar 

  • Vucic D, Deshayes K, Ackerly H, Pisabarro MT, Kadkhodayan S, Fairbrother WJ et al. (2002). SMAC negatively regulates the anti-apoptotic activity of melanoma inhibitor of apoptosis (ML-IAP). J Biol Chem 277: 12275–12279.

    CAS  PubMed  Google Scholar 

  • Vucic D, Fairbrother WJ . (2007). The inhibitor of apoptosis proteins as therapeutic targets in cancer. Clin Cancer Res 13: 5995–6000.

    CAS  PubMed  Google Scholar 

  • Vucic D, Stennicke HR, Pisabarro MT, Salvessen GS, Dixit VM . (2000). ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas. Curr Biol 10: 1359–1366.

    CAS  PubMed  Google Scholar 

  • Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ . (2001). TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412: 346–351.

    CAS  PubMed  Google Scholar 

  • Wang J, He H, Yu L, Xia HH, Lin MC, Gu Q et al. (2006a). HSF1 down-regulates XAF1 through transcriptional regulation. J Biol Chem 281: 2451–2459.

    CAS  PubMed  Google Scholar 

  • Wang J, Peng Y, Sun YW, He H, Zhu S, An X et al. (2006b). All-trans retinoic acid induces XAF1 expression through an interferon regulatory factor-1 element in colon cancer. Gastroenterology 130: 747–758.

    CAS  PubMed  Google Scholar 

  • Wang L, Du F, Wang X . (2008). TNF-alpha induces two distinct caspase-8 activation pathways. Cell 133: 693–703.

    CAS  PubMed  Google Scholar 

  • Wang Z, Cuddy M, Samuel T, Welsh K, Schimmer A, Hanaii F et al. (2004). Cellular, biochemical, and genetic analysis of mechanism of small molecule IAP inhibitors. J Biol Chem 279: 48168–48176.

    CAS  PubMed  Google Scholar 

  • Wegener E, Krappmann D . (2007). CARD-Bcl10-Malt1 signalosomes: missing link to NF-kappaB. Sci STKE 2007: pe21.

    PubMed  Google Scholar 

  • Wright ME, Han DK, Hockenbery DM . (2000). Caspase-3 and inhibitor of apoptosis protein(s) interactions in Saccharomyces cerevisiae and mammalian cells. FEBS Lett 481: 13–18.

    CAS  PubMed  Google Scholar 

  • Wu CJ, Conze DB, Li T, Srinivasula SM, Ashwell JD . (2006). Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-kappaB activation. Nat Cell Biol 8: 398–406.

    CAS  PubMed  Google Scholar 

  • Wu CJ, Conze DB, Li X, Ying SX, Hanover JA, Ashwell JD . (2005a). TNF-alpha induced c-IAP1/TRAF2 complex translocation to a Ubc6-containing compartment and TRAF2 ubiquitination. EMBO J 24: 1886–1898.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wu G, Chai J, Suber TL, Wu JW, Du C, Wang X et al. (2000). Structural basis of IAP recognition by Smac/DIABLO. Nature 408: 1008–1012.

    CAS  PubMed  Google Scholar 

  • Wu M, Yuan S, Szporn AH, Gan L, Shtilbans V, Burstein DE . (2005b). Immunocytochemical detection of XIAP in body cavity effusions and washes. Mod Pathol 18: 1618–1622.

    CAS  PubMed  Google Scholar 

  • Wu TY, Wagner KW, Bursulaya B, Schultz PG, Deveraux QL . (2003). Development and characterization of nonpeptidic small molecule inhibitors of the XIAP/caspase-3 interaction. Chem Biol 10: 759–767.

    CAS  PubMed  Google Scholar 

  • Xia Y, Novak R, Lewis J, Duckett CS, Phillips AC . (2006). Xaf1 can cooperate with TNFalpha in the induction of apoptosis, independently of interaction with XIAP. Mol Cell Biochem 286: 67–76.

    CAS  PubMed  Google Scholar 

  • Xu L, Zhu J, Hu X, Zhu H, Kim HT, LaBaer J et al. (2007). c-IAP1 cooperates with Myc by acting as a ubiquitin ligase for Mad1. Mol Cell 28: 914–922.

    CAS  PubMed  Google Scholar 

  • Yamamoto K, Abe S, Nakagawa Y, Suzuki K, Hasegawa M, Inoue M et al. (2004). Expression of IAP family proteins in myelodysplastic syndromes transforming to overt leukemia. Leuk Res 28: 1203–1211.

    CAS  PubMed  Google Scholar 

  • Yan Y, Mahotka C, Heikaus S, Shibata T, Wethkamp N, Liebmann J et al. (2004). Disturbed balance of expression between XIAP and Smac/DIABLO during tumour progression in renal cell carcinomas. Br J Cancer 91: 1349–1357.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yang D, Welm A, Bishop JM . (2004). Cell division and cell survival in the absence of survivin. Proc Natl Acad Sci USA 101: 15100–15105.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yang L, Cao Z, Yan H, Wood WC . (2003). Coexistence of high levels of apoptotic signaling and inhibitor of apoptosis proteins in human tumor cells: implication for cancer specific therapy. Cancer Res 63: 6815–6824.

    CAS  PubMed  Google Scholar 

  • Yang QH, Du C . (2004). Smac/DIABLO selectively reduces the levels of c-IAP1 and c-IAP2 but not that of XIAP and livin in HeLa cells. J Biol Chem 279: 16963–16970.

    CAS  PubMed  Google Scholar 

  • Yang Y, Fang S, Jensen JP, Weissman AM, Ashwell JD . (2000). Ubiquitin protein ligase activity of IAPs and their degradation in proteasomes in response to apoptotic stimuli. Science 288: 874–877.

    CAS  PubMed  Google Scholar 

  • Yin W, Chen N, Zhang Y, Zeng H, Chen X, He Y et al. (2006). Survivin nuclear labeling index: a superior biomarker in superficial urothelial carcinoma of human urinary bladder. Mod Pathol 19: 1487–1497.

    CAS  PubMed  Google Scholar 

  • Zender L, Spector MS, Xue W, Flemming P, Cordon-Cardo C, Silke J et al. (2006). Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 125: 1253–1267.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao Y, Conze DB, Hanover JA, Ashwell JD . (2007). Tumor necrosis factor receptor 2 signaling induces selective c-IAP1-dependent ASK1 ubiquitination and terminates mitogen-activated protein kinase signaling. J Biol Chem 282: 7777–7782.

    CAS  PubMed  Google Scholar 

  • Zheng D, Perianayagam A, Lee DH, Brannan MD, Yang LE, Tellalian D et al. (2008). AMPK activation with AICAR provokes an acute fall in plasma [K+]. Am J Physiol Cell Physiol 294: C126–C135.

    CAS  PubMed  Google Scholar 

  • Zhou H, Du MQ, Dixit VM . (2005). Constitutive NF-kappaB activation by the t(11;18)(q21;q21) product in MALT lymphoma is linked to deregulated ubiquitin ligase activity. Cancer Cell 7: 425–431.

    CAS  PubMed  Google Scholar 

  • Zou B, Chim CS, Zeng H, Leung SY, Yang Y, Tu SP et al. (2006). Correlation between the single-site CpG methylation and expression silencing of the XAF1 gene in human gastric and colon cancers. Gastroenterology 131: 1835–1843.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

RGK is a Howard Hughes Medical Institute (HHMI) International Research Scholar and a Fellow of the Royal Society of Canada. RGK is supported by funds from the Canadian Institutes of Health Research (CIHR), and the HHMI. HHC is the recipient of a Michael Cuccione Foundation and CIHR Institute of Cancer Research postdoctoral fellowship. SP and DJM are recipients of a Natural Sciences and Engineering Research Council of Canada postdoctoral fellowships. ECL is supported by funds from the Optimist Club's Campaign against Childhood Cancers.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to E C LaCasse.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

LaCasse, E., Mahoney, D., Cheung, H. et al. IAP-targeted therapies for cancer. Oncogene 27, 6252–6275 (2008). https://doi.org/10.1038/onc.2008.302

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2008.302

Keywords

  • XIAP
  • cIAP1
  • cIAP2
  • survivin
  • livin
  • birc

Further reading

Search

Quick links