Regulation of Bcl-2 expression by dihydrotestosterone in hormone sensitive LNCaP-FGC prostate cancer cells.
OBJECTIVE
Up-regulation of the anti-apoptotic bcl-2 proto-oncogene is associated with androgen independent prostate cancer progression. This observation suggests that the expression of bcl-2 may be negatively regulated by androgens in prostate cancer cells.


METHODS
The expression of the proto-oncogene bcl-2 was assessed in the hormone sensitive prostate cancer cell line LNCaP-FGC in the presence and absence of a physiological concentration of 1 nM. dihydrotestosterone (DHT). Sequence analysis of the bcl-2 promoter regions demonstrated the presence of 2 potential androgen response elements. Transient transfections of luciferase reporter constructs containing these potential androgen response elements into LNCaP-FGC cells in the presence and absence of DHT were performed. Steady-state transcripts of bcl-2 were assessed using RNase protection assays.


RESULTS
Cells cultured in charcoal stripped serum in the presence of DHT resulted in down-regulation of bcl-2 protein. Down-regulation of bcl-2 protein and mRNA by DHT was inhibited by coincubation with the antiandrogen bicalutamide, an agent that competitively inhibits binding of DHT to androgen receptor. Luciferase reporter constructs containing candidate androgen response elements were transrepressed in the presence of DHT. Bcl-2 mRNA was also down-regulated by DHT and this down-regulation could not be abolished by cycloheximide.


CONCLUSIONS
Together these results suggest that the suppression of bcl-2 expression by DHT in hormone sensitive LNCaP-FGC prostate cancer cells occurs directly. In addition, these results provide a possible mechanistic basis for the up-regulation (derepression) of bcl-2 observed in hormone independent prostate cancers.
Bruckheimer
Elizabeth M
EM
Spurgers
Kevin
K
Weigel
Nancy L
NL
Logothetis
Christopher
C
McDonnell
Timothy J
TJ
D013196:Dihydrotestosterone / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics* / Q000473:pathology; D011467:Prostate / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000235:genetics
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2; D013196:Dihydrotestosterone