Androgen-mediated resistance to apoptosis.
BACKGROUND
Previous studies demonstrate that androgen is capable of exerting a protective effect in the androgen-sensitive human prostate cancer cell line LNCaP. Limited studies, however, have addressed the underlying mechanisms involved, in particular the effects of androgen on both pro- and anti-apoptotic gene expression.


METHODS
We investigated the effects of androgen on apoptotic sensitivity and the expression of the caspases and specific members of the Bcl-2 family in the LNCaP cell line. The effects of androgen on NF-kappaB activation were also investigated by using a gel mobility shift assay.


RESULTS
5alpha-Dihydrotestosterone (5-alphaDHT) conferred resistance to radiation (5 Gy) and etoposide-induced apoptosis in the LNCaP cell line. This finding was associated with a time-dependent decrease in the expression of the caspases and pro-apoptotic Bcl-2 family members. 5-alphaDHT did not confer protection against apoptosis in the LNCaP line transfected with the IkappaB super repressor of NF-kappaB, nor in the androgen insensitive PC-3 and DU-145 cell lines.


CONCLUSIONS
The ability of 5-alphaDHT to raise the apoptotic threshold in the LNCaP cell line by altering specific pro-apoptotic gene expression suggests that androgen may serve as a general survival signal against diverse pathways that ultimately signal for apoptosis. We hypothesize that NF-kappaB serves as an important mediator in androgen survival signaling.
Coffey
Ronan N T
RN
Department of Surgery, Mater Misericordiae Hospital, University College Dublin, Dublin, Ireland. research@profsurg.iol.ie
Watson
R William G
RW
O'Neill
Amanda J
AJ
Mc Eleny
Kevin
K
Fitzpatrick
John M
JM
D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000502:physiology; D013196:Dihydrotestosterone / Q000494:pharmacology*; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D014407:Tumor Cells, Cultured
D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D013196:Dihydrotestosterone; D020169:Caspases