Androgens repress Bcl-2 expression via activation of the retinoblastoma (RB) protein in prostate cancer cells

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The oncogene Bcl-2 is upregulated frequently in prostate tumors following androgen ablation therapy, and Bcl-2 overexpression may contribute to the androgen-refractory relapse of the disease. However, the molecular mechanism underlying androgenic regulation of Bcl-2 in prostate cancer cells is understood poorly. In this study, we demonstrated that no androgen response element (ARE) was identified in the androgen-regulated region of the P1 promoter of Bcl-2 gene, whereas, we provided evidence that the androgenic effect is mediated by E2F1 protein through a putative E2F-binding site in the promoter. We further demonstrated that retinoblastoma (RB) protein plays a critical role in androgen regulation of Bcl-2. The phosphorylation levels of RB at serine residues 780 and 795 were decreased in LNCaP cells treated with androgens. Ectopic expression of a constitutively active form of RB inhibited expression of Bcl-2. Knockdown of endogenous RB protein by an Rb small inference RNA (siRNA) induced an increase in Bcl-2 levels. Most importantly, the effect of androgens on Bcl-2 was abolished completely by specific inhibition of RB function with a mutated E1A. Finally, androgen treatment of LNCaP cells upregulated specifically levels of the cyclin-dependent kinase inhibitors (CDKIs) p15INK4B and p27KIP1. Ectopic expression of p15INK4B and/or p27KIP1 inhibited Bcl-2 expression. Knockdown of endogenous p15INK4B or p27KIP1 protein with a pool of siRNAs diminished androgen-induced downregulation of Bcl-2 expression. Therefore, our data indicate that androgens suppress Bcl-2 expression through negatively modulating activities of the E2F site in the Bcl-2 promoter by activating the CDKI-RB axis.

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androgen receptor


androgen response element


retinoblastoma protein


cyclin-dependent kinase


cyclin-dependent kinase inhibitor


chromatin immunoprecipitation


small interference RNA


  1. Agus DB, Cordon-Cardo C, Fox W, Drobnjak M, Koff A, Golde DW and Scher HI . (1999). J. Natl. Cancer Inst., 91, 1869–1876.

  2. Bruckheimer EM, Spurgers K, Weigel NL, Logothetis C and McDonnell TJ . (2003). J. Urol., 169, 1553–1557.

  3. Butler R, Mitchell SH, Tindall DJ and Young CY . (2000). Cell Growth Differ., 11, 49–61.

  4. Cheema SK, Mishra SK, Rangnekar VM, Tari AM, Kumar R and Lopez-Berestein G . (2003). J. Biol. Chem., 278, 19995–20005.

  5. Chi KN, Gleave ME, Klasa R, Murray N, Bryce C, Lopes de Menezes DE, D'Aloisio S and Tolcher AW . (2001). Clin. Cancer Res., 7, 3920–3927.

  6. Colombel M, Symmans F, Gil S, O'Toole KM, Chopin D, Benson M, Olsson CA, Korsmeyer S and Buttyan R . (1993). Am. J. Pathol., 143, 390–400.

  7. Cordon-Cardo C, Koff A, Drobnjak M, Capodieci P, Osman I, Millard SS, Gaudin PB, Fazzari M, Zhang ZF, Massague J and Scher HI . (1998). J. Natl. Cancer Inst., 90, 1284–1291.

  8. Decary S, Decesse JT, Ogryzko V, Reed JC, Naguibneva I, Harel-Bellan A and Cremisi CE . (2002). Mol. Cell. Biol., 22, 7877–7888.

  9. Denmeade SR, Lin XS and Isaacs JT . (1996). Prostate, 28, 251–265.

  10. Dorai T, Goluboff ET, Olsson CA and Buttyan R . (1997a). Anticancer Res., 17, 3307–3312.

  11. Dorai T, Olsson CA, Katz AE and Buttyan R . (1997b). Prostate, 32, 246–258.

  12. Fernandez A, Udagawa T, Schwesinger C, Beecken W, Achilles-Gerte E, McDonnell T and D'Amato R . (2001). J. Natl. Cancer Inst., 93, 208–213.

  13. Gleave M . (1999). Prostate Cancer Prostatic. Dis., 2, S15.

  14. Gleave M, Tolcher A, Miyake H, Nelson C, Brown B, Beraldi E and Goldie J . (1999a). Clin. Cancer Res., 5, 2891–2898.

  15. Gleave ME, Miayake H, Goldie J, Nelson C and Tolcher A . (1999b). Urology, 54, 36–46.

  16. Gomez-Manzano C, Mitlianga P, Fueyo J, Lee HY, Hu M, Spurgers KB, Glass TL, Koul D, Liu TJ, McDonnell TJ and Yung WK . (2001). Cancer Res., 61, 6693–6697.

  17. Graff JR, Konicek BW, McNulty AM, Wang Z, Houck K, Allen S, Paul JD, Hbaiu A, Goode RG, Sandusky GE, Vessella RL and Neubauer BL . (2000). J. Biol. Chem., 275, 24500–24505.

  18. Green DR . (2000). Cell, 102, 1–4.

  19. Grossmann ME, Huang H and Tindall DJ . (2001). J. Natl. Cancer Inst., 93, 1687–1697.

  20. Haldar S, Basu A and Croce CM . (1997). Cancer Res., 57, 229–233.

  21. Hiyama H, Iavarone A and Reeves SA . (1998). Oncogene, 16, 1513–1523.

  22. Huang H, Cheville JC, Pan Y, Roche PC, Schmidt LJ and Tindall DJ . (2001). J. Biol. Chem., 276, 38830–38836.

  23. Huang H, Reed CP, Zhang JS, Shridhar V, Wang L and Smith DI . (1999). Cancer Res., 59, 2981–2988.

  24. Huang H and Tindall DJ . (2002). Crit. Rev. Eukaryot. Gene Expr., 12, 193–207.

  25. Huggins C and Hodge CV . (1941). Cancer Res., 1, 293–297.

  26. Isaacs JT . (1984). Prostate, 5, 545–557.

  27. Jiang Z and Zacksenhaus E . (2002). J. Cell. Biol., 156, 185–198.

  28. Johnson DG, Ohtani K and Nevins JR . (1994). Genes Dev., 8, 1514–1525.

  29. Kimura K, Markowski M, Bowen C and Gelmann EP . (2001). Cancer Res., 61, 5611–5618.

  30. Krajewska M, Krajewski S, Epstein JI, Shabaik A, Sauvageot J, Song K, Kitada S and Reed JC . (1996). Am. J. Pathol., 148, 1567–1576.

  31. Kyprianou N, English HF and Isaacs JT . (1990). Cancer Res., 50, 3748–3753.

  32. Lapointe J, Fournier A, Richard V and Labrie C . (1999). Endocrinology, 140, 416–421.

  33. Li JM, Nichols MA, Chandrasekharan S, Xiong Y and Wang XF . (1995). J. Biol. Chem., 270, 26750–26753.

  34. Liu SL, Rand A, Kelm Jr RJ and Getz MJ . (2000). Oncogene, 19, 3352–3362.

  35. Lu L, Schulz H and Wolf DA . (2002). BMC Cell Biol., 3, 22.

  36. Masiello D, Cheng S, Bubley GJ, Lu ML and Balk SP . (2002). J. Biol. Chem., 277, 26321–26326.

  37. McDonnell TJ, Navone NM, Troncoso P, Pisters LL, Conti C, von Eschenbach AC, Brisbay S and Logothetis CJ . (1997). J. Urol., 157, 569–574.

  38. McDonnell TJ, Troncoso P, Brisbay SM, Logothetis C, Chung LW, Hsieh JT, Tu SM and Campbell ML . (1992). Cancer Res., 52, 6940–6944.

  39. Miyake H, Tolcher A and Gleave ME . (1999). Cancer Res., 59, 4030–4034.

  40. Miyashita T, Harigai M, Hanada M and Reed JC . (1994). Cancer Res., 54, 3131–3135.

  41. Murillo H, Huang H, Schmidt LJ, Smith DI and Tindall DJ . (2001). Endocrinology, 142, 4795–4805.

  42. Neuman E, Flemington EK, Sellers WR and Kaelin Jr WG . (1994). Mol. Cell. Biol., 14, 6607–6615.

  43. Raffo AJ, Perlman H, Chen MW, Day ML, Streitman JS and Buttyan R . (1995). Cancer Res., 55, 4438–4445.

  44. Seto M, Jaeger U, Hockett RD, Graninger W, Bennett S, Goldman P and Korsmeyer SJ . (1988). EMBO J., 7, 123–131.

  45. Swinnen JV, Ulrix W, Heyns W and Verhoeven G . (1997). Proc. Natl. Acad. Sci. USA, 94, 12975–12980.

  46. Tsihlias J, Zhang W, Bhattacharya N, Flanagan M, Klotz L and Slingerland J . (2000). Oncogene, 19, 670–679.

  47. Tsujimoto Y and Croce CM . (1986). Proc. Natl. Acad. Sci. USA, 83, 5214–5218.

  48. Vigo E, Muller H, Prosperini E, Hateboer G, Cartwright P, Moroni MC and Helin K . (1999). Mol. Cell. Biol., 19, 6379–6395.

  49. Weinmann AS, Bartley SM, Zhang T, Zhang MQ and Farnham PJ . (2001). Mol. Cell. Biol., 21, 6820–6832.

  50. Westin P, Stattin P, Damber JE and Bergh A . (1995). Am. J. Pathol., 146, 1368–1375.

  51. Wilson BE, Mochon E and Boxer LM . (1996). Mol. Cell. Biol., 16, 5546–5556.

  52. Yang RM, Naitoh J, Murphy M, Wang HJ, Phillipson J, deKernion JB, Loda M and Reiter RE . (1998). J. Urol., 159, 941–945.

  53. Zegarra-Moro OL, Schmidt LJ, Huang H and Tindall DJ . (2002). Cancer Res., 62, 1008–1013.

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We thank Drs LM Boxer, RJ Kelm, JR Nevins, and Z Zacksenhaus for plasmids. This work was supported in part by a grant (DK60920) from the National Institutes of Health and a grant from the TJ Martell Foundation (DJT), and a developmental award of the Mayo Prostate Cancer SPORE (CA91956) funded by the National Cancer Institute (HH).

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Correspondence to Donald J Tindall.

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  • androgen receptor
  • Bcl-2
  • RB
  • transcription regulation
  • prostate cancer

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