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

Haojie Huang, Ofelia L. Zegarra-Moro, Douglas Benson, Donald J. Tindall

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

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 p27KTP1. 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.

Original languageEnglish (US)
Pages (from-to)2161-2176
Number of pages16
JournalOncogene
Volume23
Issue number12
DOIs
StatePublished - Mar 18 2004

Keywords

  • Androgen receptor
  • Bcl-2
  • Prostate cancer
  • RB
  • Transcription regulation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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