Journal of Molecular Histology

, Volume 37, Issue 5–7, pp 183–188 | Cite as

Clusterin and DNA repair: a new function in cancer for a key player in apoptosis and cell cycle control

  • B. Shannan
  • M. Seifert
  • D. A. Boothman
  • W. Tilgen
  • J. ReichrathEmail author
Original Paper


The glycoprotein clusterin (CLU), has two known isoforms generated in human cells. A nuclear form of CLU protein (nCLU) is pro-apoptotic, while a secretory form (sCLU) is pro-survival. Both forms are implicated in various cell functions, including DNA repair, cell cycle regulation, and apoptotic cell death. CLU expression has been associated with tumorigenesis and the progression of various malignancies. In response to DNA damage, cell survival can be enhanced by activation of DNA repair mechanisms, while simultaneously stimulating energy-expensive cell cycle checkpoints that delay the cell cycle progression to allow more time for DNA repair. This review summarizes our current understanding of the role of clusterin in DNA repair, apoptosis, and cell cycle control and the relevance.


Clusterin DNA repair Double strand break Apoptosis Cell cycle control 



This work was supported in part by grant DE-FG02–06ER64186 to DAB.


  1. Berardi P, Russell M, El-Osta A et al (2004) Functional links between transcription and apoptosis. Cell Mol Life Sci 61:2173–2180PubMedCrossRefGoogle Scholar
  2. Bettuzzi S, Scorcioni F, Astancolle S et al (2002) Clusterin (SGP-2) transient overexpression decreases proliferation rate of SV40-immortalized human prostate epithelial cells by slowing down cell cycle progression. Oncogene 21:4328–4334PubMedCrossRefGoogle Scholar
  3. Cervellera M, Raschella G, Santilli G et al (2000) Direct transactivation of the antiapoptotic gene apolipoprotein J (clusterin) by B-MYB. J Biol Chem 275:21055–21060PubMedCrossRefGoogle Scholar
  4. Chen TY, Chen JS, Su WC et al (2005) Expression of DNA repair gene ku80 in lymphoid neoplasm. Eur J Haematol 74:481–488PubMedCrossRefGoogle Scholar
  5. Chow TY, Choudhury SA (2005) DNA repair protein: endo-exonuclease as a new frontier in cancer therapy. Future Oncol 1:265–271PubMedCrossRefGoogle Scholar
  6. Criswell T, Klokov D, Beman M, Lavik JP, Boothman DA (2003) Repression of IR-inducible clusterin expression by the p53 tumour suppressor protein. Cancer Biol Ther 2:372–380PubMedGoogle Scholar
  7. Criswell T, Beman M, Araki S, Leskov K, Cataldo E, Mayp LD, Boothman DA (2005) Delayed activation of insulin-like growth factor-1 receptor/SrcMAPK/Egr-1 signaling regulates clusterin expression, a pro-survival factor. J Biol Chem 280:14212–14221PubMedCrossRefGoogle Scholar
  8. 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 23:38–46PubMedCrossRefGoogle Scholar
  9. Gleave M, Miyake H, Chi K (2005) Beyond simple castration: targeting the molecular basis of treatment resistance in advanced prostate cancer. Cancer Chemother Pharmacol 56:47–57PubMedCrossRefGoogle Scholar
  10. Gleave M, Nelson C, Chi K (2003) Antisense targets to enhance hormone and cytotoxic therapies in advanced prostate cancer. Curr Drug Targets 4:209–221PubMedCrossRefGoogle Scholar
  11. Hara I, Miyake H, Gleave ME et al (2001) Introduction of clusterin gene into human renal cell carcinoma cells enhances their resistance to cytotoxic chemotherapy through inhibition of apoptosis both in vitro and in vivo. Jpn J Cancer Res 92:1220–1224PubMedGoogle Scholar
  12. July LV, Beraldi E, So A, Fazil L et al (2004) Nucleotide-based therapies targeting clusterin chemosensitized human lung adenocarcinoma cells both in vitro and in vivo. Mol Cancer Ther 3:223–232PubMedGoogle Scholar
  13. Lakins J, Bennett SA, Chen JH et al (1998) Clusterin biogenesis is altered during apoptosis in the regressing rat ventral prostate. J Biol Chem 273:27887–27895PubMedCrossRefGoogle Scholar
  14. Leskov K, Criswell T, Antonino S et al (2001) When X-ray-inducible proteins meet DNA double strand break repair. Semin Radiat Oncol 11:352–372PubMedCrossRefGoogle Scholar
  15. Leskov K, Klokov D, Li J et al (2003) Synthesis functional analyses of nuclear clusterin, a cell death protein. J Biol Chem 278:11590–11600PubMedCrossRefGoogle Scholar
  16. Li L, Zou L (2005) Sensing, signaling, and responding to DNA damage: organization of the checkpoint pathways in mammalian cells. J Cell Biochem 1:298–306CrossRefGoogle Scholar
  17. Miyake H, Nelson C, Rennie PS et al (2000) Testosterone-repressed prostate message-2 is an antiapoptotic agent involved in progression to androgen independence in prostate cancer. Cancer Res 60:170–176PubMedGoogle Scholar
  18. Miyake H, Hara I, Kamidono S et al (2001) Synergistic chemosensitization and inhibition of tumor growth and metastasis by the antisense oligonucleotides targeting clusterin gene in a human bladder cancer model. Clin Cancer Res 7:4245–4252PubMedGoogle Scholar
  19. Miyake H, Hara I, Kamidono S et al (2003) Resistance to cytotoxic chemotherapy induced apoptosis in human prostate cancer cells is associated with intracellular clusterin expression. Oncol Rep 10:469–473PubMedGoogle Scholar
  20. Miyake H, Hara I, Gleave ME et al (2004) Protection of androgen-dependent human prostate cancer cells from oxidative stress-induced DNA damage by overexpression of clusterin and its modulation by androgen. Prostate 61:318–323PubMedCrossRefGoogle Scholar
  21. Montpetit ML, Lawless KR, Tenniswood M (1986) Androgen-repressed messages in the rat ventral prostate. Prostate 8:25–36PubMedGoogle Scholar
  22. Osborne JE, Hutchinson PE (2002) Vitamin D and systemic cancer: is this relevant to malignant melanoma? Br J Dermatol 147:197–213PubMedCrossRefGoogle Scholar
  23. Pajak B, Orzechowski A (2006) Clusterin: the missing link in the calcium-dependent resistance of cancer cells to apopogenic stimuli. Postepy Hig Med Dosw 60:45–51Google Scholar
  24. Pucci S, Bonnano E, Pichiorri F et al (2004) Modulation of different clusterin isoforms in human colon tumorigenesis. Oncogene 23:2298–2304PubMedCrossRefGoogle Scholar
  25. Shah MA, Schwartz GK (2003) Cyclin-dependent kinases as targets for cancer therapy. Cancer Chemother Biol Response Modif 21:145–170PubMedGoogle Scholar
  26. Shannan B, Seifert M, Leskov K et al (2006) Challenge and promise: roles for clusterin in pathogenesis, progression and therapy for cancer. Cell Death Differ 13:12–19PubMedCrossRefGoogle Scholar
  27. Sutton D, Kim S, Shuai X et al (2006) Efficient suppression of secretory clusterin levels by polymer-siRNA nanocomplexes enhances ionizing radiation lethality in human MCF-7 breast cancer cells in vitro. Int J Nanomedicine 1:155–162CrossRefGoogle Scholar
  28. Trougakos IP, Gonos ES (2002) Clusterin/apolipoprotein J in human aging and cancer. Int J Biochem Cell Biol 34:1430–1448PubMedCrossRefGoogle Scholar
  29. Trougakos IP, So A, Jansen B et al (2004) Silencing expression of the clusterin/apolipoprotein J gene in human cancer cells using small interfering RNA induces spontaneous apoptosis, reduced growth ability, and cell sensitization to genotoxic and oxidative stress. Cancer Res 64:1834–1842PubMedCrossRefGoogle Scholar
  30. van Weelden K, Flanagan L, Binderup L et al (1998) Apoptotic regression of MCF-7 xenografts in nude mice treated with the vitamin D3 analogue, EB1089. Endocrinology 139:2102–2110CrossRefGoogle Scholar
  31. Yang CR, Yeh S, Leskov K et al (1999) Isolation of Ku70-binding proteins (KUBs). Nucleic Acids Res 27:2165–2174PubMedCrossRefGoogle Scholar
  32. Zellweger T, Miyake H, Cooper S, Chi K, Conklin BS, Monia BP, Gleave ME (2001) Antitumor activity of antisense clusterin oligonucleotides is improved in vitro and in vivo by incorporation of 2′-O-(2-methoxy)ethyl chemistry. J Pharmacol Exp Ther 298:934–940PubMedGoogle Scholar
  33. Zellweger T, Chi K, Miyake H et al (2002) Enhanced radiosensitivity in prostate cancer by inhibition of the cell survival protein clusterin. Clin Cancer Res 8:3276–3284PubMedGoogle Scholar
  34. Zellweger T, Kiyama S, Chi K et al (2003) Overexpression of the cytoprotective protein clusterin decreases radiosensitivity in human LNCaP prostate tumour model. BJU Int 92:463–469PubMedCrossRefGoogle Scholar
  35. Zhang H, Kim JK, Edwards CA et al (2005) Clusterin inhibits apoptosis by interacting with activated Bax. Nat Cell Biol 7:909–115PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • B. Shannan
    • 1
  • M. Seifert
    • 1
  • D. A. Boothman
    • 2
  • W. Tilgen
    • 1
  • J. Reichrath
    • 1
    Email author
  1. 1.Department of DermatologyThe Saarland University HospitalHomburg/Saar Germany
  2. 2.Department of Oncology, Laboratory of Molecular Stress ResponsesUniversity of Texas Southwestern Medical CenterDallasUSA

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