Although there is no shortage of potential targets for cancer therapeutics, we know of only a handful of molecules that are differentially expressed in cancer and intersect multiple pathways required for tumour maintenance. Survivin embodies these properties, and orchestrates integrated cellular networks that are essential for tumour cell proliferation and viability. Pursuing the nodal functions of survivin in cancer might lead to the development of global pathway inhibitors with unique therapeutic potential.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Vogelstein, B. & Kinzler, K. W. Cancer genes and the pathways they control. Nature Med. 10, 789–799 (2004).
Leaf, C. Why we're losing the war on cancer (and how to win it). Fortune 149, 76–97 (2004).
Sawyers, C. Targeted cancer therapy. Nature 432, 294–297 (2004).
van der Greef, J. & McBurney, R. N. Rescuing drug discovery: in vivo systems pathology and systems pharmacology. Nature Rev. Drug Discov. 4, 961–967 (2005).
Citri, A. & Yarden, Y. EGF–ERBB signalling: towards the systems level. Nature Rev. Mol. Cell Biol. 7, 505–516 (2006).
Isaacs, J. S., Xu, W. & Neckers, L. Heat shock protein 90 as a molecular target for cancer therapeutics. Cancer Cell 3, 213–217 (2003).
Altieri, D. C. The case for survivin as a regulator of microtubule dynamics and cell-death decisions. Curr. Opin. Cell Biol. 18, 609–615 (2006).
Eckelman, B. P., Salvesen, G. S. & Scott, F. L. Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family. EMBO Rep. 7, 988–994 (2006).
Lens, S. M., Vader, G. & Medema, R. H. The case for Survivin as mitotic regulator. Curr. Opin. Cell Biol. 18, 616–622 (2006).
Fukuda, S. & Pelus, L. M. Survivin, a cancer target with an emerging role in normal adult tissues. Mol. Cancer Ther. 5, 1087–1098 (2006).
Stauber, R. H., Mann, W. & Knauer, S. K. Nuclear and cytoplasmic survivin: molecular mechanism, prognostic, and therapeutic potential. Cancer Res. 67, 5999–6002 (2007).
Mirza, A. et al. Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway. Oncogene 21, 2613–2622 (2002).
Esteve, P. O., Chin, H. G. & Pradhan, S. Human maintenance DNA (cytosine-5)-methyltransferase and p53 modulate expression of p53-repressed promoters. Proc. Natl Acad. Sci. USA 102, 1000–1005 (2005).
Verdecia, M. A. et al. Structure of the human anti-apoptotic protein survivin reveals a dimeric arrangement. Nature Struct. Biol. 7, 602–608 (2000).
Fortugno, P. et al. Survivin exists in immunochemically distinct subcellular pools and is involved in spindle microtubule function. J. Cell Sci. 115, 575–585 (2002).
O'Connor, D. S. et al. Regulation of apoptosis at cell division by p34cdc2 phosphorylation of survivin. Proc. Natl Acad. Sci. USA 97, 13103–13107 (2000).
Vong, Q. P., Cao, K., Li, H. Y., Iglesias, P. A. & Zheng, Y. Chromosome alignment and segregation regulated by ubiquitination of survivin. Science 310, 1499–1504 (2005).
Li, F. & Brattain, M. G. Role of the Survivin gene in pathophysiology. Am. J. Pathol. 169, 1–11 (2006).
Velculescu, V. E. et al. Analysis of human transcriptomes. Nature Genet. 23, 387–388 (1999).
Tran, J. et al. A role for survivin in chemoresistance of endothelial cells mediated by VEGF. Proc. Natl Acad. Sci. USA 99, 4349–4354 (2002).
Morgillo, F., Woo, J. K., Kim, E. S., Hong, W. K. & Lee, H. Y. Heterodimerization of insulin-like growth factor receptor/epidermal growth factor receptor and induction of survivin expression counteract the antitumor action of erlotinib. Cancer Res. 66, 10100–10111 (2006).
Paik, S. et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N. Engl. J. Med. 351, 2817–2826 (2004).
Smith, S. D. et al. Urine detection of survivin and diagnosis of bladder cancer. JAMA 285, 324–328 (2001).
Fesik, S. W. Promoting apoptosis as a strategy for cancer drug discovery. Nature Rev. Cancer. 5, 876–885 (2005).
Carvalho, A., Carmena, M., Sambade, C., Earnshaw, W. C. & Wheatley, S. P. Survivin is required for stable checkpoint activation in taxol-treated HeLa cells. J. Cell Sci. 116, 2987–2998 (2003).
Tulu, U. S., Fagerstrom, C., Ferenz, N. P. & Wadsworth, P. Molecular requirements for kinetochore-associated microtubule formation in mammalian cells. Curr. Biol. 16, 536–541 (2006).
Sampath, S. C. et al. The chromosomal passenger complex is required for chromatin-induced microtubule stabilization and spindle assembly. Cell 118, 187–202 (2004).
Speliotes, E. K., Uren, A., Vaux, D. & Horvitz, H. R. The survivin-like C. elegans BIR-1 protein acts with the Aurora-like kinase AIR-2 to affect chromosomes and the spindle midzone. Mol. Cell 6, 211–223 (2000).
Jones, G., Jones, D., Zhou, L., Steller, H. & Chu, Y. Deterin, a new inhibitor of apoptosis from Drosophila melanogaster. J. Biol. Chem. 275, 22157–22165 (2000).
Walter, D., Wissing, S., Madeo, F. & Fahrenkrog, B. The inhibitor-of-apoptosis protein Bir1p protects against apoptosis in S. cerevisiae and is a substrate for the yeast homologue of Omi/HtrA2. J. Cell Sci. 119, 1843–1851 (2006).
Dohi, T., Beltrami, E., Wall, N. R., Plescia, J. & Altieri, D. C. Mitochondrial survivin inhibits apoptosis and promotes tumorigenesis. J. Clin. Invest. 114, 1117–1127 (2004).
Lamb, J. The Connectivity Map: a new tool for biomedical research. Nature Rev. Cancer 7, 54–60 (2007).
Adams, R. R., Carmena, M. & Earnshaw, W. C. Chromosomal passengers and the (aurora) ABCs of mitosis. Trends Cell Biol. 11, 49–54 (2001).
Jeyaprakash, A. A. et al. Structure of a survivin–borealin-INCENP core complex reveals how chromosomal passengers travel together. Cell 131, 271–285 (2007).
Vanoosthuyse, V., Prykhozhij, S. & Hardwick, K. G. Shugoshin 2 regulates localization of the chromosomal passenger proteins in fission yeast mitosis. Mol. Biol. Cell 18, 1657–1669 (2007).
Stoepel, J., Ottey, M. A., Kurischko, C., Hieter, P. & Luca, F. C. The mitotic exit network Mob1p–Dbf2p kinase complex localizes to the nucleus and regulates passenger protein localization. Mol. Biol. Cell 16, 5465–5479 (2005).
Wheatley, S. P., Henzing, A. J., Dodson, H., Khaled, W. & Earnshaw, W. C. Aurora-B phosphorylation in vitro identifies a residue of survivin that is essential for its localization and binding to inner centromere protein (INCENP) in vivo. J. Biol. Chem. 279, 5655–5660 (2004).
Mollinari, C. et al. The mammalian passenger protein TD-60 is an RCC1 family member with an essential role in prometaphase to metaphase progression. Dev. Cell 5, 295–307 (2003).
Sandall, S. et al. A Bir1–Sli15 complex connects centromeres to microtubules and is required to sense kinetochore tension. Cell 127, 1179–1191 (2006).
Ghosh, J. C., Dohi, T., Raskett, C. M., Kowalik, T. F. & Altieri, D. C. Activated checkpoint kinase 2 provides a survival signal for tumor cells. Cancer Res. 66, 11576–11579 (2006).
Hoffman, W. H., Biade, S., Zilfou, J. T., Chen, J. & Murphy, M. Transcriptional repression of the anti-apoptotic survivin gene by wild type p53. J. Biol. Chem. 277, 3247–3257 (2002).
Okada, H. et al. Survivin loss in thymocytes triggers p53-mediated growth arrest and p53-independent cell death. J. Exp. Med. 199, 399–410 (2004).
Rosa, J., Canovas, P., Islam, A., Altieri, D. C. & Doxsey, S. J. Survivin modulates microtubule dynamics and nucleation throughout the cell cycle. Mol. Biol. Cell 17, 1483–1493 (2006).
Allan, L. A. & Clarke, P. R. Phosphorylation of caspase-9 by CDK1/cyclin B1 protects mitotic cells against apoptosis. Mol. Cell 26, 301–310 (2007).
O'Connor, D. S., Wall, N. R., Porter, A. C. & Altieri, D. C. A p34cdc2 survival checkpoint in cancer. Cancer Cell 2, 43–54 (2002).
Goga, A., Yang, D., Tward, A. D., Morgan, D. O. & Bishop, J. M. Inhibition of CDK1 as a potential therapy for tumors over-expressing MYC. Nature Med. 13, 820–827 (2007).
Zhang, T. et al. Evidence that APC regulates survivin expression: a possible mechanism contributing to the stem cell origin of colon cancer. Cancer Res. 61, 8664–8667 (2001).
Semba, S. et al. Fhit modulation of the Akt-survivin pathway in lung cancer cells: Fhit-tyrosine 114 (Y114) is essential. Oncogene 25, 2860–2872 (2006).
Xu, Z. X. et al. Promyelocytic leukemia protein 4 induces apoptosis by inhibition of survivin expression. J. Biol. Chem. 279, 1838–1844 (2004).
Kim, P. J., Plescia, J., Clevers, H., Fearon, E. R. & Altieri, D. C. Survivin and molecular pathogenesis of colorectal cancer. Lancet 362, 205–209 (2003).
Gritsko, T. et al. Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin. Cancer Res. 12, 11–19 (2006).
Jiang, Y., Saavedra, H. I., Holloway, M. P., Leone, G. & Altura, R. A. Aberrant regulation of survivin by the RB/E2F family of proteins. J. Biol. Chem. 279, 40511–40520 (2004).
Gu, L., Chiang, K. Y., Zhu, N., Findley, H. W. & Zhou, M. Contribution of STAT3 to the activation of survivin by GM-CSF in CD34+ cell lines. Exp. Hematol. 35, 957–966 (2007).
Vaira, V. et al. Regulation of survivin expression by IGF-1/mTOR signaling. Oncogene 26, 2678–2684 (2007).
Asanuma, H. et al. Survivin expression is regulated by coexpression of human epidermal growth factor receptor 2 and epidermal growth factor receptor via phosphatidylinositol 3-kinase/AKT signaling pathway in breast cancer cells. Cancer Res. 65, 11018–11025 (2005).
Kang, B. H. & Altieri, D. C. Regulation of survivin stability by the aryl hydrocarbon receptor-interacting protein. J. Biol. Chem. 281, 24721–24727 (2006).
Fortugno, P. et al. Regulation of survivin function by Hsp90. Proc. Natl Acad. Sci. USA 100, 13791–13796 (2003).
Marusawa, H. et al. HBXIP functions as a cofactor of survivin in apoptosis suppression. EMBO J. 22, 2729–2740 (2003).
Dohi, T., Xia, F. & Altieri, D. C. Compartmentalized phosphorylation of IAP by protein kinase A regulates cytoprotection. Mol. Cell 27, 17–28 (2007).
Samuel, T. et al. cIAP1 Localizes to the nuclear compartment and modulates the cell cycle. Cancer Res. 65, 210–218 (2005).
Caldas, H. et al. Survivin splice variants regulate the balance between proliferation and cell death. Oncogene 24, 1994–2007 (2005).
Sun, C., Nettesheim, D., Liu, Z. & Olejniczak, E. T. Solution structure of human survivin and its binding interface with Smac/Diablo. Biochemistry 44, 11–17 (2005).
Song, Z., Yao, X. & Wu, M. Direct interaction between survivin and Smac/DIABLO is essential for the anti-apoptotic activity of survivin during taxol-induced apoptosis. J. Biol. Chem. 278, 23130–23140 (2003).
Ceballos-Cancino, G., Espinosa, M., Maldonado, V. & Melendez-Zajgla, J. Regulation of mitochondrial Smac/DIABLO-selective release by survivin. Oncogene 26, 7569–7575 (2007).
Wang, H. W., Sharp, T. V., Koumi, A., Koentges, G. & Boshoff, C. Characterization of an anti-apoptotic glycoprotein encoded by Kaposi's sarcoma-associated herpesvirus which resembles a spliced variant of human survivin. EMBO J. 21, 2602–2615 (2002).
Vogel, C., Hager, C. & Bastians, H. Mechanisms of mitotic cell death induced by chemotherapy-mediated G2 checkpoint abrogation. Cancer Res. 67, 339–345 (2007).
You, R. I. et al. Inhibition of lymphotoxin-β receptor-mediated cell death by survivin-ΔEx3. Cancer Res. 66, 3051–3061 (2006).
Xia, F. & Altieri, D. C. Mitosis-independent survivin gene expression in vivo and regulation by p53. Cancer Res. 66, 3392–3395 (2006).
van 't Veer, L. J. et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 415, 530–536 (2002).
Tolcher, A. W. et al. A phase I study of YM155, a novel survivin suppressant, administered by 168 hour continuous infusion to patients with advanced solid tumors (ASCO Annual Meeting abstract). J. Clin. Oncol. 24, 3014 (2006).
Chang, C. C., Heller, J. D., Kuo, J. & Huang, R. C. 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 (2004).
Wobser, M. et al. Complete remission of liver metastasis of pancreatic cancer under vaccination with a HLA-A2 restricted peptide derived from the universal tumor antigen survivin. Cancer Immunol. Immunother. 55, 1294–1298 (2006).
Plescia, J. et al. Rational design of shepherdin, a novel anticancer agent. Cancer Cell 7, 457–468 (2005).
Nakagawa, K. et al. Phase I study of YM155, a first-in-class survivin suppressant, in patients with advanced solid tumors in Japan (ASCO Annual Meeting abstract). J. Clin. Oncol. 25, 3536 (2007).
Jonkers, J. & Berns, A. Oncogene addiction: sometimes a temporary slavery. Cancer Cell 6, 535–538 (2004).
Uren, A. G. et al. Survivin and the inner centromere protein INCENP show similar cell-cycle localization and gene knockout phenotype. Curr. Biol. 10, 1319–1328 (2000).
Xing, Z., Conway, E. M., Kang, C. & Winoto, A. Essential role of survivin, an inhibitor of apoptosis protein, in T-cell development, maturation, and homeostasis. J. Exp. Med. 199, 69–80 (2004).
Jiang, Y. et al. Essential role for survivin in early brain development. J. Neurosci. 25, 6962–6970 (2005).
Zwerts, F. et al. Lack of endothelial cell survivin causes embryonic defects in angiogenesis, cardiogenesis, and neural tube closure. Blood 109, 4742–4752 (2007).
Leung, C. G. et al. Requirements for survivin in terminal differentiation of erythroid cells and maintenance of hematopoietic stem and progenitor cells. J. Exp. Med. 204, 1603–1611 (2007).
Chen, J. S. et al. Cancer-specific activation of the survivin promoter and its potential use in gene therapy. Cancer Gene Ther. 11, 740–747 (2004).
Altieri, D.C. Targeted therapy by disabling crossroad signaling networks: the survivin paradigm. Mol. Cancer Ther. 5, 478–482 (2006).
Ambrosini, G., Adida, C. & Altieri, D. C. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nature Med. 3, 917–921 (1997).
Li, F. et al. Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 396, 580–584 (1998).
Adida, C., Berrebi, D., Peuchmaur, M., Reyes-Mugica, M. & Altieri, D. C. Anti-apoptosis gene, survivin, and prognosis of neuroblastoma. Lancet 351, 882–883 (1998).
Fraser, A. G., James, C., Evan, G. I. & Hengartner, M. O. Caenorhabditis elegans inhibitor of apoptosis protein (IAP) homologue BIR-1 plays a conserved role in cytokinesis. Curr. Biol. 9, 292–301 (1999).
Li, F. et al. Pleiotropic cell-division defects and apoptosis induced by interference with survivin function. Nature Cell Biol. 1, 461–466 (1999).
Chantalat, L. et al. Crystal structure of human survivin reveals a bow tie-shaped dimer with two unusual α-helical extensions. Mol. Cell 6, 183–189 (2000).
Kanwar, J. R., Shen, W. P., Kanwar, R. K., Berg, R. W. & Krissansen, G. W. Effects of survivin antagonists on growth of established tumors and b7–1 immunogene therapy. J. Natl Cancer Inst. 93, 1541–1552 (2001).
Mesri, M., Wall, N. R., Li, J., Kim, R. W. & Altieri, D. C. Cancer gene therapy using a survivin mutant adenovirus. J. Clin. Invest. 108, 981–990 (2001).
Bao, R. et al. Activation of cancer-specific gene expression by the survivin promoter. J. Natl Cancer Inst. 94, 522–528 (2002).
Lens, S. M. et al. Survivin is required for a sustained spindle checkpoint arrest in response to lack of tension. EMBO J. 22, 2934–2947 (2003).
Dohi, T. et al. An IAP–IAP complex inhibits apoptosis. J. Biol. Chem. 279, 34087–34090 (2004).
Hirschowitz, E. A. et al. Autologous dendritic cell vaccines for non-small-cell lung cancer. J. Clin. Oncol. 22, 2808–2815 (2004).
Tsuruma, T. et al. Phase I clinical study of anti-apoptosis protein, survivin-derived peptide vaccine therapy for patients with advanced or recurrent colorectal cancer. J. Transl. Med. 2, 19 (2004).
Xiang, R. et al. A DNA vaccine targeting survivin combines apoptosis with suppression of angiogenesis in lung tumor eradication. Cancer Res. 65, 553–561 (2005).
Idenoue, S. et al. A potent immunogenic general cancer vaccine that targets survivin, an inhibitor of apoptosis proteins. Clin. Cancer Res. 11, 1474–1482 (2005).
Xia, W. et al. Regulation of survivin by ErbB2 signaling: therapeutic implications for ErbB2-overexpressing breast cancers. Cancer Res. 66, 1640–1647 (2006).
Dasgupta, P. et al. Nicotine inhibits apoptosis induced by chemotherapeutic drugs by up-regulating XIAP and survivin. Proc. Natl Acad. Sci. USA 103, 6332–6337 (2006).
Taubert, H. et al. Stem cell-associated genes are extremely poor prognostic factors for soft-tissue sarcoma patients. Oncogene 26, 7170–7174 (2007).
Song, J., Salek-Ardakani, S., So, T. & Croft, M. The kinases aurora B and mTOR regulate the G1–S cell cycle progression of T lymphocytes. Nature Immunol. 8, 64–73 (2007).
I apologize to all the colleagues whose work on survivin could not be cited owing to space constraints. I thank C. W. Lee for discussion and Ingenuity Pathway Analysis. This work was supported by National Institutes of Health grants.
About this article
Cite this article
Altieri, D. Survivin, cancer networks and pathway-directed drug discovery. Nat Rev Cancer 8, 61–70 (2008). https://doi.org/10.1038/nrc2293
Breast Cancer Research (2021)
Scientific Reports (2021)
Cell Death & Disease (2021)
Identification of important genes and drug repurposing based on clinical-centered analysis across human cancers
Acta Pharmacologica Sinica (2021)
Identifying intracellular signaling modules and exploring pathways associated with breast cancer recurrence
Scientific Reports (2021)