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Genetic inactivation of ApoJ/clusterin: effects on prostate tumourigenesis and metastatic spread

Oncogene volume 28, pages 4344–4352 (2009)Cite this article

Abstract

ApoJ/Clusterin (CLU) is a heterodimeric protein localized in the nucleus, cytoplasm or secretory organelles and involved in cell survival and neoplastic transformation. Its function in human cancer is still highly controversial. In this study, we examined the prostate of mice in which CLU has been genetically inactivated. Surprisingly, we observed transformation of the prostate epithelium in the majority of CLU knockout mice. Either PIN (prostate intraepithelial neoplasia) or differentiated carcinoma was observed in 100 and 87% of mice with homozygous or heterozygous deletion of CLU, respectively. Crossing CLU knockout with TRAMP (prostate cancer prone) mice results in a strong enhancement of metastatic spread. Finally, CLU depletion causes tumourigenesis in female TRAMP mice, which are normally cancer free. Mechanistically, deletion of CLU induces activation of nuclear factor-kB, a potentially oncogenic transcription factor important for the proliferation and survival of prostate cells.

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References

  • Bettuzzi S, Hiipakka RA, Gilna P, Liao ST . (1989). Identification of an androgen-repressed mRNA in rat ventral prostate as coding for sulphated glycoprotein 2 by cDNA cloning and sequence analysis. Biochem J 257: 293–296.

    Article  CAS  Google Scholar 

  • Caccamo AE, Scaltriti M, Caporali A, D’Arca D, Corti A, Corvetta D et al. (2005). Ca2+ depletion induces nuclear clusterin, a novel effector of apoptosis in immortalized human prostate cells. Cell Death Differ 12: 101–104.

    Article  CAS  Google Scholar 

  • Caccamo AE, Scaltriti M, Caporali A, D’Arca D, Scorcioni F, Candiano G et al. (2003). Nuclear translocation of a clusterin isoform is associated with induction of anoikis in SV40-immortalized human prostate epithelial cells. Ann NY Acad Sci 1010: 514–519.

    Article  CAS  Google Scholar 

  • Caporali A, Davalli P, Astancolle S, D’Arca D, Brausi M, Bettuzzi S et al. (2004). The chemopreventive action of catechins in the TRAMP mouse model of prostate carcinogenesis is accompanied by clusterin over-expression. Carcinogenesis 25: 2217–2224.

    Article  CAS  Google Scholar 

  • Chayka O, Corvetta D, Dews M, Caccamo AE, Piotrowska I, Santilli G et al. (2009). Clusterin, a haploinsufficient tumor suppressor gene in neuroblastomas. J Natl Cancer Inst 101: 663–677.

    Article  CAS  Google Scholar 

  • Chen CD, Sawyers CL . (2002). NF-kappa B activates prostate-specific antigen expression and is upregulated in androgen-independent prostate cancer. Mol Cell Biol 22: 2862–2870.

    Article  CAS  Google Scholar 

  • Chen T, Turner J, McCarthy S, Scaltriti M, Bettuzzi S, Yeatman TJ . (2004). Clusterin-mediated apoptosis is regulated by adenomatous polyposis coli and is p21 dependent but p53 independent. Cancer Res 64: 7412–7419.

    Article  CAS  Google Scholar 

  • Chiaverotti T, Couto SS, Donjacour A, Mao JH, Nagase H, Cardiff RD et al. (2008). Dissociation of epithelial and neuroendocrine carcinoma lineages in the transgenic adenocarcinoma of mouse prostate model of prostate cancer. Am J Pathol 172: 236–246.

    Article  CAS  Google Scholar 

  • Cussenot O, Berthon P, Berger R, Mowszowicz I, Faille A, Hojman F et al. (1991). Immortalization of human adult normal prostatic epithelial cells by liposomes containing large T-SV40 gene. J Urol 146: 881–886.

    Article  CAS  Google Scholar 

  • Fritz IB, Burdzy K, Setchell B, Blaschuk O . (1983). Ram rete testis fluid contains a protein (clusterin) which influences cell-cell interactions in vitro. Biol Reprod 28: 1173–1188.

    Article  CAS  Google Scholar 

  • Gleave M, Miyake H . (2005). Use of antisense oligonucleotides targeting the cytoprotective gene, clusterin, to enhance androgen- and chemo-sensitivity in prostate cancer. World J Urol 23: 38–46.

    Article  CAS  Google Scholar 

  • Greenberg NM, DeMayo F, Finegold MJ, Medina D, Tilley WD, Aspinall JO et al. (1995). Prostate cancer in a transgenic mouse. Proc Natl Acad Sci USA 92: 3439–3443.

    Article  CAS  Google Scholar 

  • Hellebrekers DM, Melotte V, Vire E, Langenkamp E, Molema G, Fuks F et al. (2007). Identification of epigenetically silenced genes in tumor endothelial cells. Cancer Res 67: 4138–4148.

    Article  CAS  Google Scholar 

  • Ito K, Bernardi R, Morotti A, Matsuoka S, Saglio G, Ikeda Y et al. (2008). PML targeting eradicates quiescent leukaemia-initiating cells. Nature 453: 1072–1078.

    Article  CAS  Google Scholar 

  • Jones SE, Jomary C . (2002). Clusterin. Int J Biochem Cell Biol 34: 427–431.

    Article  CAS  Google Scholar 

  • July LV, Akbari M, Zellweger T, Jones EC, Goldenberg SL, Gleave ME . (2002). Clusterin expression is significantly enhanced in prostate cancer cells following androgen withdrawal therapy. Prostate 50: 179–188.

    Article  CAS  Google Scholar 

  • Kaplan-Lefko PJ, Chen TM, Ittmann MM, Barrios RJ, Ayala GE, Huss WJ et al. (2003). Pathobiology of autochthonous prostate cancer in a pre-clinical transgenic mouse model. Prostate 55: 219–237.

    Article  Google Scholar 

  • Lau SH, Sham JS, Xie D, Tzang CH, Tang D, Ma N et al. (2006). Clusterin plays an important role in hepatocellular carcinoma metastasis. Oncogene 25: 1242–1250.

    Article  CAS  Google Scholar 

  • McLaughlin L, Zhu G, Mistry M, Ley-Ebert C, Stuart WD, Florio CJ et al. (2000). Apolipoprotein J/clusterin limits the severity of murine autoimmune myocarditis. J Clin Invest 106: 1105–1113.

    Article  CAS  Google Scholar 

  • Miyake H, Muramaki M, Kurahashi T, Yamanaka K, Hara I, Gleave M et al. (2006). Expression of clusterin in prostate cancer correlates with Gleason score but not with prognosis in patients undergoing radical prostatectomy without neoadjuvant hormonal therapy. Urology 68: 609–614.

    Article  Google Scholar 

  • Miyake H, Nelson C, Rennie PS, Gleave ME . (2000). Testosterone-repressed prostate message-2 is an antiapoptotic gene involved in progression to androgen independence in prostate cancer. Cancer Res 60: 170–176.

    CAS  PubMed  Google Scholar 

  • Morris EJ, Ji JY, Yang F, Di Stefano L, Herr A, Moon NS et al. (2008). E2F1 represses beta-catenin transcription and is antagonized by both pRB and CDK8. Nature 455: 552–556.

    Article  CAS  Google Scholar 

  • Nizard P, Tetley S, Le Drean Y, Watrin T, Le Goff P, Wilson MR et al. (2007). Stress-induced retrotranslocation of clusterin/ApoJ into the cytosol. Traffic 8: 554–565.

    Article  CAS  Google Scholar 

  • Nomura T, Yamasaki M, Nomura Y, Mimata H . (2005). Expression of the inhibitors of apoptosis proteins in cisplatin-resistant prostate cancer cells. Oncol Rep 14: 993–997.

    CAS  PubMed  Google Scholar 

  • Nuutinen T, Suuronen T, Kyrylenko S, Huuskonen J, Salminen A . (2005). Induction of clusterin/apoJ expression by histone deacetylase inhibitors in neural cells. Neurochem Int 47: 528–538.

    Article  CAS  Google Scholar 

  • Rauhala HE, Porkka KP, Saramaki OR, Tammela TL, Visakorpi T . (2008). Clusterin is epigenetically regulated in prostate cancer. Int J Cancer 123: 1601–1609.

    Article  CAS  Google Scholar 

  • Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D et al. (2004). ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 6: 1–6.

    Article  CAS  Google Scholar 

  • Santilli G, Aronow BJ, Sala A . (2003). Essential requirement of apolipoprotein J (clusterin) signaling for IkappaB expression and regulation of NF-kappaB activity. J Biol Chem 278: 38214–38219.

    Article  CAS  Google Scholar 

  • Scaltriti M, Brausi M, Amorosi A, Caporali A, D’Arca D, Astancolle S et al. (2004). Clusterin (SGP-2, ApoJ) expression is downregulated in low- and high-grade human prostate cancer. Int J Cancer 108: 23–30.

    Article  CAS  Google Scholar 

  • Shannan B, Seifert M, Leskov K, Willis J, Boothman D, Tilgen W et al. (2006). Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer. Cell Death Differ 13: 12–19.

    Article  CAS  Google Scholar 

  • Shukla S, MacLennan GT, Fu P, Patel J, Marengo SR, Resnick MI et al. (2004). Nuclear factor-kappaB/p65 (Rel A) is constitutively activated in human prostate adenocarcinoma and correlates with disease progression. Neoplasia 6: 390–400.

    Article  CAS  Google Scholar 

  • Shukla S, Maclennan GT, Marengo SR, Resnick MI, Gupta S . (2005). Constitutive activation of P I3 K-Akt and NF-kappaB during prostate cancer progression in autochthonous transgenic mouse model. Prostate 64: 224–239.

    Article  CAS  Google Scholar 

  • Suh J, Rabson AB . (2004). NF-kappaB activation in human prostate cancer: important mediator or epiphenomenon? J Cell Biochem 91: 100–117.

    Article  CAS  Google Scholar 

  • Thomas-Tikhonenko A, Viard-Leveugle I, Dews M, Wehrli P, Sevignani C, Yu D et al. (2004). Myc-transformed epithelial cells down-regulate clusterin, which inhibits their growth in vitro and carcinogenesis in vivo. Cancer Res 64: 3126–3136.

    Article  CAS  Google Scholar 

  • Trougakos IP, Gonos ES . (2002). Clusterin/apolipoprotein J in human aging and cancer. Int J Biochem Cell Biol 34: 1430–1448.

    Article  CAS  Google Scholar 

  • Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin Jr AS . (1998). NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 281: 1680–1683.

    Article  CAS  Google Scholar 

  • Wu ZH, Miyamoto S . (2008). Induction of a pro-apoptotic ATM-NF-kappaB pathway and its repression by ATR in response to replication stress. EMBO J 27: 1963–1973.

    Article  CAS  Google Scholar 

  • Zhang H, Kim JK, Edwards CA, Xu Z, Taichman R, Wang CY . (2005). Clusterin inhibits apoptosis by interacting with activated Bax. Nat Cell Biol 7: 909–915.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Marina Gardinam for her help with the interpretation of the pathological sections. This work was supported by grants from the Association for International Cancer Research (AICR Grant No. 06-711) to SB and AS; FIL 2008, University of Parma to SB; Sport Aiding Medical Research for Kids (SPARKS) to AS.

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Authors and Affiliations

  1. Department of Experimental Medicine, University of Parma, Parma, Italy

    S Bettuzzi, S Davoli, F Rizzi & L Belloni

  2. Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy

    P Davalli, D Pellacani, G Fregni, S Astancolle & A Corti

  3. Molecular Haematology and Cancer Biology Unit, Institute of Child Health, London, UK

    O Chayka & A Sala

  4. Department of Urology, Thomas Jefferson University, Philadelphia, PA, USA

    M Fassan & R Baffa

  5. Research, MedImmune LLC, Gaithersburg, MD, USA

    R Baffa

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  1. S Bettuzzi
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  2. P Davalli
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  3. S Davoli
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  4. O Chayka
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  11. A Corti
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  12. R Baffa
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  13. A Sala
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Corresponding authors

Correspondence to S Bettuzzi or A Sala.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Bettuzzi, S., Davalli, P., Davoli, S. et al. Genetic inactivation of ApoJ/clusterin: effects on prostate tumourigenesis and metastatic spread. Oncogene 28, 4344–4352 (2009). https://doi.org/10.1038/onc.2009.286

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  • DOI: https://doi.org/10.1038/onc.2009.286

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