PTEN tumor suppressor and androgen receptor (AR) play important roles in prostate tumorigenesis by exerting opposite effects on prostate cancer (PCa) cells. Our studies demonstrated a mutual repression and selective dominance between PTEN and AR in the growth and the apoptosis of PCa cells. On one hand, PTEN and an inhibitor of 1-phosphoinositide 3-kinase (PI3K) repressed the transcriptional activity of AR as well as androgen-induced cell proliferation and production of prostate specific antigen. On the other hand, androgen protected PCa cells from PTEN-induced apoptosis in an AR-dependent manner. While the repression of the transcriptional activity of AR by PTEN is likely to involve the down regulation of AKT, androgen protects PCa cells from PTEN-induced apoptosis without an effect on AKT activity, demonstrating a differential involvement of AKT in antagonism between PTEN and AR. Our further investigation showed that the AR and FKHR (fork head in rhabdomyosarcoma), a mammalian homologue of the C. elegans Forkhead transcription factor Daf-16, forms a complex in PCa cells after androgen treatment and the complex formation resulted in the inhibition of FKHR transcriptional activity. Since we showed that AR is more active in the absence of functional PTEN, the loss of PTEN may induce prostate tumorigenesis by exposing prostate epithelial cells to unopposed AR activity. Similarly, excessive androgens may induce prostate tumorigenesis by blocking the apoptosis-promoting function of PTEN. Our data showing that the induction of apoptosis by the restored PTEN expression in LNCaP cells only occurred in the absence of androgens, imply that PTEN mutation or decreased expression may contribute to the resistance of PCa to androgen ablation and that the combinational inhibition of both PI3K/AKT and AR signaling could be an affective approach for the treatment of AR-positive PCa. The proposed studies are to elucidate the mechanism underlying the PTEN repression of AR activity by dissecting the biochemical steps between PTEN and AR and, through the study of AR-FKHR interaction, to define the mechanism underlying the androgen protection of PCa cells from PTEN-induced apoptosis. The studies about the mechanism underlying the AR-PTEN antagonism may provide a molecular foundation for new strategies to prevent prostate tumorigenesis or to treat the hormone refractory PCa by PTEN-based gene therapy.
