Resveratrol Inhibits IL-6-Induced Transcriptional Activity of AR and STAT3 in Human Prostate Cancer LNCaP-FGC Cells

Abstract

Prostate cancer is the most frequently diagnosed cancer. Although prostate tumors respond to androgen ablation therapy at an early stage, they often acquire the potential of androgen-independent growth. Elevated transcriptional activity of androgen receptor (AR) and/or signal transducer and activator of transcription-3 (STAT3) contributes to the proliferation of prostate cancer cells. In the present study, we examined the effect of resveratrol, a phytoalexin present in grapes, on the reporter gene activity of AR and STAT3 in human prostate cancer (LNCaP-FGC) cells stimulated with interleukin-6 (IL-6) and/or dihydrotestosterone (DHT). Our study revealed that resveratrol suppressed the growth of LNCaP-FGC cells in a time- and concentration-dependent manner. Whereas the AR transcriptional activity was induced by treatment with either IL-6 or DHT, the STAT3 transcriptional activity was induced only by treatment with IL-6 but not with DHT. Resveratrol significantly attenuated IL-6-induced STAT3 transcriptional activity, and DHT- or IL-6-induced AR transcriptional activity. Treatment of cells with DHT plus IL-6 significantly increased the AR transcriptional activity as compared to DHT or IL-6 treatment alone and resveratrol markedly diminished DHT plus IL-6-induced AR transcriptional activity. Furthermore, the production of prostate-specific antigen (PSA) was decreased by resveratrol in the DHT-, IL-6- or DHT plus IL-6-treated LNCaP-FGC cells. Taken together, the inhibitory effects of resveratrol on IL-6- and/or DHT-induced AR transcriptional activity in LNCaP prostate cancer cells are partly mediated through the suppression of STAT3 reporter gene activity, suggesting that resveratrol may be a promising therapeutic choice for the treatment of prostate cancer.

Mechanisms of action of nonpeptide hormones on resveratrol‐induced antiproliferation of cancer cells

“…Resveratrol has been shown to reduce the levels of circulating androgen precursors, but it has no effect on testosterone, DHT, or prostate‐specific antigen (PSA) levels or prostate volume . Resveratrol also inhibits the dimerization of AR and the interleukin (IL)‐6–induced transcriptional activity of AR and STAT3 in human prostate cancer LNCaP‐FGC cells . Resveratrol treatment in AR + prostate cancer LNCaP cells induces a decrease in AR levels in a concentration‐dependent manner up to 150 μM .…”

“…It prompts autophagy‐mediated cell death in PC3 and DU145 cells through the regulation of SOCE mechanisms, which include downregulation of STIM1 expression and triggering of endoplasmic reticulum stress by depleting endoplasmic reticulum calcium pools . Resveratrol inhibits STAT3 activation induced by IL‐6 and/or DHT, which induces AR transcriptional activity in LNCaP prostate cancer cells . In addition, resveratrol has been reported to inhibit hypoxia‐inducible factor‐1α (HIF‐1α)–mediated AR signaling and repress tumor progression in castration‐resistant prostate cancer .…”

Natural Compounds in Prostate Cancer Prevention and Treatment: Mechanisms of Action and Molecular Targets

“…It was found to target the AR axis in different in vitro and in vivo PCa models [47][48][49][50][51]. On one hand, in LNCaP cells it inhibited β-catenin nuclear translocation through hypoxia-inducible factor 1-α (HIF-1α) downregulation, thus suppressing β-catenin-mediated AR signaling [52]; similarly, it also repressed interleukin-6 (IL-6)-induced AR transcriptional activity [53]. On the other hand, in 22RV1 cells it promoted the AR splice variant ARV7 proteasomal degradation, by enhancing its polyubiquitination.…”

Biological Activities of Resveratrol against Cancer

“…Dhar revealed that RSV downregulated metastasis associated protein 1 (MTA1), a PTEN inhibitor thereby causing inhibition of AKT pathway and hence controlling prostate cancer progression [145]. In LNCaP-FGC cells, when RSV treatment showed the inhibition of IL-6/DHT (Interlukin-6/dihydrotestosterone) induced androgen receptor (AR) transcriptional activity and partly mediated through suppression of STAT-3 reporter gene activity to hinder prostate cancer [146]. RSV along with other wine polyphenols showed anti-proliferative effects and induction of apoptosis in LNCaP cells via reduced expression of androgen receptor (AR) and caspase -3-7 [147].…”