Androgen receptor-dependent regulation of Bcl-xL expression: Implication in prostate cancer progression.
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.
Sun
Aijing
A
Department of Pathology, Shaoxing People's Hospital & the First Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang, China.
Tang
Jianxi
J
Hong
Yan
Y
Song
Jiawu
J
Terranova
Paul F
PF
Thrasher
J Brantley
JB
Svojanovsky
Stan
S
Wang
Hong-gang
HG
Li
Benyi
B
D000728:Androgens / Q000378:metabolism; D000818:Animals; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D056742:Cyclin D2; D016213:Cyclins / Q000378:metabolism; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009919:Orchiectomy; D011401:Promoter Regions, Genetic / Q000502:physiology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D011944:Receptors, Androgen / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics*
C410798:AR protein, human; D000728:Androgens; C494811:BCL2L1 protein, human; C080336:CCND2 protein, human; D056742:Cyclin D2; D016213:Cyclins; D011944:Receptors, Androgen; D051020:bcl-X Protein