Em. Bruckheimer et N. Kyprianou, Dihydrotestosterone enhances transforming growth factor-ss-induced apoptosis in hormone-sensitive prostate cancer cells, ENDOCRINOL, 142(6), 2001, pp. 2419-2426
In this study, the potential interactions between dihydrotestosterone (DHT)
, a survival factor, and transforming growth factor-beta (TGF-beta), an apo
ptotic inducer, were examined in a derivative of the hormone-sensitive pros
tate cancer cell line LNCaP. The LNCaP TGF-beta receptor II cells, engineer
ed to express TGF-beta receptor II, are sensitive to both DHT and TGF-beta.
Surprisingly, when the LNCaP TGF-beta receptor II cells were treated with
TGF-beta in the presence of physiological levels of DHT, both cell cycle ar
rest and apoptosis induction were significantly enhanced over TGF-beta alon
e. This effect temporally correlated with an increased expression of the ce
ll cycle regulator p21 as well as the apoptotic executioner, procaspase-1,
and a parallel down-regulation of the antiapoptotic protein, bcl-2. Express
ion of bar and caspase-3 proteins remained unchanged following treatment. F
urthermore, apoptosis induction was suppressed by the caspase-1 inhibitor,
z-YVAD, but not the caspase-3 inhibitor, z-DQMD, thus demonstrating the fun
ctional significance of increased procaspase-1 expression in TGF-beta -medi
ated apoptosis in prostate cancer cells. These results indicate that TGF-be
ta -mediated apoptosis can actually be enhanced by androgens through specif
ic mechanisms involving cell cycle and apoptosis regulators and provide ini
tial evidence on the ability of physiological levels of androgens to stimul
ate the intrinsic apoptotic potential of prostate cancer cells. Therefore,
this study provides a molecular basis for the priming of prostate cancer ce
lls for maximal apoptosis induction, during hormone-ablation therapy.