Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Tamoxifen Suppresses Clusterin Level through Akt Inactivation and Proteasome Degradation in Human Prostate Cancer Cells

  • Published : 2009.01.31
Download PDF
⟨ Previous Next ⟩

Abstract

Clusterin is a heterodimeric sulfated glycoprotein and plays a role in many different types of cancer as a cell survival factor and helps cancerous cells to evade stress-induced apoptosis. To investigate whether the regulation of clusterin expression is involved in the mechanism of anticancer agent, we studied the effect of tamoxifen on clusterin expression in human prostate cancer PC-3 cells. Treatment of PC-3 cells with tamoxifen reduced cellular proliferation. Western blot analyses showed that treatment with tamoxifen suppressed clusterin expression in a concentration-dependent manner. Transfection with clusterin siRNA plasmid showed that clusterin is required for PC-3 cell survival. We found that tamoxifen resulted in a rapid decrease in the phosphorylation of Akt on Ser473 leading to prevent kinase activity. Expression of myristoylated Akt prevented tamoxifen-mediated clusterin downregulation. Interestingly, MG132, a wellknown proteasome inhibitor also recovered clusterin expression suppressed by tamoxifen. These data indicate that clusterin expression may be regulated by activation of Akt and ubiquitin-proteasome pathway plays an important role in tamoxifen-mediated clusterin suppression.

Keywords

References

  1. Ammar H. and Closset, J. L. (2008). Clusterin activates survival through the phosphatidylinositol 3-kinase/Akt pathway. J. Biol. Chem. 283, 12851-12861 https://doi.org/10.1074/jbc.M800403200
  2. Bettuzzi, S., Scorcioni, F., Astancolle, S., Davalli, P., Scaltriti, M. and Corti, A. (2002). Clusterin (SGP-2) transient overexpression decreases proliferation rate of SV40-immortalized human prostate epithelial cells by slowing down cell cycle progression. Oncogene 21, 4328-4334 https://doi.org/10.1038/sj.onc.1205594
  3. Blaschuk, O., Burdzy, K. and Fritz, I. B. (1983). Purification and characterization of a cell-aggregating factor (clusterin), the major glycoprotein in ram rete testis fluid. J. Biol. Chem. 258, 7714-7720
  4. Brunet, A., Bonni, A., Zigmond, M. J., Lin, M. Z., Juo, P., Hu, L. S., Anderson, M. J., Arden, K. C., Blenis, J. and Greenberg, M. E. (1999). Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857-868 https://doi.org/10.1016/S0092-8674(00)80595-4
  5. Caccamo, A. E., Scaltriti, M., Caporali, A., D'Arca, D., Scorcioni, F., Candiano, G., Mangiola, M. and Bettuzzi, S. (2003). Nuclear translocation of a clusterin isoform is associated with induction of anoikis in SV40-immortalized human prostate epithelial cells. Ann. N Y Acad. Sci. 1010, 514-519 https://doi.org/10.1196/annals.1299.095
  6. Cervellera, M., Raschella, G., Santilli, G., Tanno, B., Ventura, A., Mancini, C., Sevignani, C., Calabretta, B. and Sala, A. (2000). Direct transactivation of the anti-apoptotic gene apolipoprotein J (clusterin) by B-MYB. J. Biol. Chem. 275, 21055-21060 https://doi.org/10.1074/jbc.M002055200
  7. Chen, X., Halberg, R. B., Ehrhardt, W. M., Torrealba, J. and Dove, W. F. (2003). Clusterin as a biomarker in murine and human intestinal neoplasia. Proc. Natl. Acad. Sci. USA. 100, 9530-9535 https://doi.org/10.1073/pnas.1233633100
  8. Clark, A. S., West, K., Streicher, S. and Dennis, P. A. (2002). Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol. Cancer Ther. 1, 707-717
  9. Collard, M. W. and Griswold, M. D. (1987). Biosynthesis and molecular cloning of sulfated glycoprotein 2 secreted by rat Sertoli cells. Biochemistry 26, 3297-3303 https://doi.org/10.1021/bi00386a008
  10. Dan, H. C., Sun, M., Kaneko, S., Feldman, R. I., Nicosia, S. V., Wang, H. G., Tsang, B. K. and Cheng, J. Q. (2004). Akt phosphorylation and stabilization of X-linked inhibitor of apoptosis protein (XIAP). J. Biol. Chem. 279, 5405-5412 https://doi.org/10.1074/jbc.M312044200
  11. Dumont, P., Chainiaux, F., Eliaers, F., Petropoulou, C., Remacle, J., Koch-Brandt, C., Gonos, E. S. and Toussaint, O. (2002). Overexpression of apolipoprotein J in human fibroblasts protects against cytotoxicity and premature senescence induced by ethanol and tert-butylhydroperoxide. Cell Stress Chaperones 7, 23-35 https://doi.org/10.1379/1466-1268(2002)007<0023:OOAJIH>2.0.CO;2
  12. El Etreby, M. F., Liang, Y. and Lewis, R. W. (2000). Induction of apoptosis by mifepristone and tamoxifen in human LNCaP prostate cancer cells in culture. Prostate 43, 31-42 https://doi.org/10.1002/(SICI)1097-0045(20000401)43:1<31::AID-PROS5>3.0.CO;2-#
  13. Feng, J., Tamaskovic, R., Yang, Z., Brazil, D. P., Merlo, A., Hess, D. and Hemmings, B. A. (2004). Stabilization of Mdm2 via decreased ubiquitination is mediated by protein kinase B/Akt-dependent phosphorylation. J. Biol. Chem. 279, 35510-35517 https://doi.org/10.1074/jbc.M404936200
  14. Gleave, M. E., Miyake, H., Zellweger, T., Chi, K., July, L., Nelson, C. and Rennie, P. (2001). Use of antisense oligonucleotides targeting the antiapoptotic gene, clusterin/testosterone-repressed prostate message 2, to enhance androgen sensitivity and chemosensitivity in prostate cancer. Urology 58, 39-49 https://doi.org/10.1016/S0090-4295(01)01241-9
  15. Hilt, W. and Wolf, D. H. (1996). Proteasomes: destruction as a programme. Trends Biochem. Sci. 21, 96-102 https://doi.org/10.1016/S0968-0004(96)10012-8
  16. Jones, S. E. and Jomary, C. (2002). Clusterin. Int. J. Biochem. Cell. Biol. 34, 427-431 https://doi.org/10.1016/S1357-2725(01)00155-8
  17. Jordan, N. J., Gee, J. M., Barrow, D., Wakeling, A. E. and Nicholson, R. I. (2004). Increased constitutive activity of PKB/Akt in tamoxifen resistant breast cancer MCF-7 cells. Breast Cancer Res Treat. 87,167-180 https://doi.org/10.1023/B:BREA.0000041623.21338.47
  18. Jordan, V. C. (2006). Tamoxifen (ICI46,474) as a targeted therapy to treat and prevent breast cancer. Br. J. Pharmacol. 147, S269-S276 https://doi.org/10.1038/sj.bjp.0706399
  19. Jordan, V. C. (2007). Chemoprevention of breast cancer with selective oestrogen-receptor modulators. Nat. Rev. Cancer 7, 46-53 https://doi.org/10.1038/nrc2048
  20. Kennedy, S. G., Wagner, A. J., Conzen, S. D., Jordan, J., Bellacosa, A., Tsichlis, P. N. and Hay, N. (1997). The PI3-kinase/Akt signaling pathway delivers an anti-apoptotic signal. Genes Dev. 11, 701-713 https://doi.org/10.1101/gad.11.6.701
  21. Kuo, C. C., Liu, J. F., Shiah, H. S., Ma, L. C. and Chang, J. Y. (2007) Tamoxifen accelerates proteasomal degradation of $O^6$-methylguanine DNA methyltransferase in human cancer cells. Int. J. Cancer 121, 2293-2300 https://doi.org/10.1002/ijc.22927
  22. Leskov, K. S., Klokov, D. Y., Li, J., Kinsella, T. J. and Boothman, D. A. (2003). Synthesis and functional analyses of nuclear clusterin, a cell death protein. J. Biol. Chem. 278, 11590-11600 https://doi.org/10.1074/jbc.M209233200
  23. Miyake, H., Hara, I., Gleave, M. E. and Eto, H. (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, 318-323 https://doi.org/10.1002/pros.20087
  24. Miyake, H., Nelson, C., Rennie, P. S. and Gleave, M. E. (2000). Testosterone expressed prostate message-2 is an antiapoptotic gene involved in progression to androgen independence in prostate cancer. Cancer Res. 60, 170-176
  25. Petropoulou, C., Trougakos, I. P., Kolettas, E., Toussaint, O. and Gonos, E. S. (2001). Clusterin/apolipoprotein J is a novel biomarker of cellular senescence that does not affect the proliferative capacity of human diploid fibroblasts. FEBS Lett. 509, 287-297 https://doi.org/10.1016/S0014-5793(01)03150-7
  26. Ranney, M. K., Ahmed, I. S. A., Potts, K. R. and Craven, R. J. (2007). Multiple pathways regulating the anti-apoptotic protein clusterin in breast cancer. Biochim. Biophys. Acta. 1772, 1103-1111 https://doi.org/10.1016/j.bbadis.2007.06.004
  27. So, A., Sinnemann, S., Huntsman, D., Fazli, L. and Gleave, M. (2005). Knockdown of the cytoprotective chaperone, clusterin, chemosensitizes human breast cancer cells both in vitro and in vivo. Mol. Cancer Ther. 4, 1837-1849 https://doi.org/10.1158/1535-7163.MCT-05-0178
  28. Sowery, R. D., Hadaschik, B. A., So, A. I., Zoubeidi, A., Fazli, L., Hurtado-Coll, A. and Gleave, M. E. (2008). Clusterin knockdown using the antisense oligonucleotide OGX-11 re-sensitizes docetaxel-refractory prostate cancer PC-3 cells to chemotherapy. BJU Int. 102, 389-397 https://doi.org/10.1111/j.1464-410X.2008.07618.x
  29. Tanno, B., Negroni, A., Vitali, R., Pirozzoli, M. C., Cesi, V., Mancini, C., Calabretta, B. and Raschellà, G. (2002). Expression of insulin-like growth factor-binding protein 5 in neuroblastoma cells is regulated at the transcriptional level by c-Myb and B-Myb via direct and indirect mechanisms. J. Biol. Chem. 277, 23172-23180 https://doi.org/10.1074/jbc.M200141200
  30. Trougakos, I. P., Lourda, M., Agiostratidou, G., Kletsas, D. and Gonos, E. S. (2005). Differential effects of clusterin/apolipoprotein J on cellular growth and survival. Free Radic. Biol. Med. 38, 436-449 https://doi.org/10.1016/j.freeradbiomed.2004.10.038
  31. Trougakos, I. P., So, A., Jansen, B., Gleave, M. E. and Gonos, E. S. (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, 1834-1842 https://doi.org/10.1158/0008-5472.CAN-03-2664
  32. Tsubuki, S., Kawasaki, H., Saito, Y., Miyashita, N., Inomata, M. and Kawashima, S. (1993). Purification and characterization of a Z-Leu-Leu-Leu-MCA degrading protease expected to regulate neurite formation: a novel catalytic activity in proteasome. Biochem. Biophys. Res. Commun. 196, 1195-1201 https://doi.org/10.1006/bbrc.1993.2378
  33. Wilson, M. R. and Easterbrook-Smith, S. B. (2000). Clusterin is a secreted mammalian chaperone. Trends Biochem. Sci. 25, 95-98 https://doi.org/10.1016/S0968-0004(99)01534-0
  34. Yoo, Y. A., Kim, Y. H., Kim, J. S. and Seo, J. H. (2008). The functional implications of Akt activity and TGF-${\beta}$ signaling in tamoxifen-resistant breast cancer. Biochim. Biophys. Acta. 1783, 438-447 https://doi.org/10.1016/j.bbamcr.2007.12.001
  35. Zellweger, T., Chi, K., Miyake, H., Adomat, H., Kiyama, S., Skov, K. and Gleave, M. E. (2002). Enhanced radiosensitivity in prostate cancer by inhibition of the cell survival protein clusterin. Clin. Cancer Res. 8, 3276-3284
  36. Zhang, H., Kim, J. K., Edwards, C. A., Xu, Z., Taichman, R. and Wang, C. Y. (2005). Clusterin inhibits apoptosis by interacting with activated Bax. Nat. Cell Biol. 7, 909-915 https://doi.org/10.1038/ncb1291
  37. Zhou, H., Li, X.-M., Meinkoth, J. and Pittman, R. N. (2000). Akt regulates cell survival and apoptosis at a postmitochondrial level. J. Cell. Biol. 151, 483-494 https://doi.org/10.1083/jcb.151.3.483

Cited by

  1. Cross-regulation between protein L-isoaspartyl O-methyltransferase and ERK in epithelial mesenchymal transition of MDA-MB-231 cells vol.32, pp.9, 2011, https://doi.org/10.1038/aps.2011.94
  2. Knockdown of Clusterin Expression Increases the In Vitro Sensitivity of Human Prostate Cancer Cells to Paclitaxel vol.77, pp.22-24, 2014, https://doi.org/10.1080/15287394.2014.951760