Androgen receptor-dependent regulation of Bcl-xL expression: Implication in prostate cancer progression

Aijing Sun, Jianxi Tang, Yan Hong, Jiawu Song, Paul F. Terranova, J. Brantley Thrasher, Stan Svojanovsky, Hong Gang Wang, Benyi Li

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30 Scopus citations

Abstract

BACKGROUND. Recently we reported that silencing the androgen receptor (AR) gene reduced Bcl-xL expression that was associated with a profound apoptotic cell death in prostate cancer cells. In this study we further investigated AR-regulated Bcl-xL expression. METHODS. Prostate cancer cell line LNCaP and its sublines, LNCaP/PURO and LNCaP/Bclxl, were used for cell proliferation assay and xenograft experiments in nude mice. Luciferase gene reporters driven by mouse or human bcl-x gene promoter were used to determine androgen regulation of Bcl-xL expression. RT-PCR and Western blot assays were conducted to assess Bcl-xL gene expression. Chromatin immunoprecipitation assay was performed to determine AR interaction with Bcl-xL promoter. Bcl-xL-induced alteration of gene expression was examined using cDNA microarray assay. RESULTS. In cultured prostate cancer LNCaP cells, androgen treatment significantly increased Bcl-xL expression at mRNA and protein levels via an AR-dependent mechanism. Promoter analyses demonstrated that the AR mediated androgen-stimulated bcl-x promoter activation and that the AR interacted with bcl-x promoter. Enforced expression of Bcl-xL gene dramatically increased cell proliferation in vitro and promoted xenograft tumor growth in vivo. Genome-wide gene profiling analysis revealed that Bcl-xL expression was significantly higher in metastatic and castration-resistant diseases compared to normal prostate tissues or primary cancers. Bcl-xL overexpression significantly increased the expression of cyclin D2, which might be responsible for Bcl-xL-induced cell proliferation and tumor growth. CONCLUSIONS. Taken together, our data strongly suggest that androgen stimulates Bcl-xL expression via the AR and that increased Bcl-xL expression plays a versatile role in castration-resistant progression of prostate cancer.

Original languageEnglish (US)
Pages (from-to)453-461
Number of pages9
JournalProstate
Volume68
Issue number4
DOIs
Publication statusPublished - Mar 1 2008

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All Science Journal Classification (ASJC) codes

  • Oncology
  • Urology

Cite this

Sun, A., Tang, J., Hong, Y., Song, J., Terranova, P. F., Thrasher, J. B., ... Li, B. (2008). Androgen receptor-dependent regulation of Bcl-xL expression: Implication in prostate cancer progression. Prostate, 68(4), 453-461. https://doi.org/10.1002/pros.20723