The tumor suppressor gene
PTEN (phosphatase and
tensin homolog deleted on chromosome 10) and the
androgen receptor (AR) play important roles in
tumor development and progression in prostate
carcinogenesis. Among many functions, PTEN negatively regulates the cytoplasmic
phosphatidylinositol-3-kinase/AKT anti-apoptotic pathway; and nuclear PTEN affects the cell cycle by also negatively regulating the MAPK pathway via
cyclin D. Decreased PTEN expression is correlated with
prostate cancer progression. Over-expression of AR and upregulation of AR transcriptional activity are often observed in the later stages of
prostate cancer. Recent studies indicate that PTEN regulates AR activity and stability. However, the mechanism of how AR regulates PTEN has never been studied. Furthermore,
resveratrol, a phytoalexin enriched in red grapes, strawberries and peanuts, has been shown to inhibit AR transcriptional activity in
prostate cancer cells. In this study, we use
prostate cancer cell lines to test the hypothesis that
resveratrol inhibits cellular proliferation in both AR-dependent and -independent mechanisms. We show that
resveratrol inhibits AR transcriptional activity in both
androgen-dependent and -independent
prostate cancer cells. Additionally,
resveratrol stimulates PTEN expression through AR inhibition. In contrast,
resveratrol directly binds
epidermal growth factor receptor (EGFR) rapidly inhibiting EGFR phosphorylation, resulting in decreased AKT phosphorylation, in an AR-independent manner. Thus,
resveratrol may act as potential adjunctive treatment for late-stage
hormone refractory
prostate cancer. More importantly, for the first time, our study demonstrates the mechanism by which AR regulates PTEN expression at the transcription level, indicating the direct link between a
nuclear receptor and the PI3K/AKT pathway.