Mechanisms Involved in Resveratrol‐Induced Apoptosis and Cell Cycle Arrest in Prostate Cancer—Derived Cell Lines

Abstract

Resveratrol is a polyphenol found at high concentrations in grapes and red wine with reported anticarcinogenic effects. We studied the molecular mechanism of resveratrol-induced apoptosis and proliferation arrest in prostate derived cells PZ-HPV-7 (nontumorigenic line), LNCaP (androgen-sensitive cancer line), and PC-3 (androgen-insensitive cancer line). Apoptosis and cell cycle distribution were evaluated by flow cytometry and proliferation by MTT assay and direct cell counting. Caspases, bax, bcl-2, cyclins, Cdks, p53, p21, and p27 were measured by Western blot and kinase activities of cyclin/Cdk complexes by immunoprecipitation followed by kinase assays with appropriate substrates. Resveratrol induced a decrease in proliferation rates and an increase in apoptosis in cancer cell lines in a dose-and time-dependent manner. These effects were coincident with cell accumulation at the G0/G1 phase. In LNCaP and PC-3, the apoptosis induced by resveratrol was mediated by activation of caspases 9 and 3 and a change in the ratio of bax/bcl-2. Expressions of cyclin D1, E, and Cdk4 as well as cyclin D1/Cdk4 kinase activity were reduced by resveratrol only in LNCaP cells. In contrast, cyclin B and Cdk1 expression and cyclin B/ Cdk1 kinase activity were decreased in both cell lines in the presence of resveratrol. However, modulator proteins p53, p21, and p27 were increased by resveratrol only in LNCaP cells. These effects probably result in the observed proliferation arrest and disruption of cell cycle control. In addition, the specific differences found between LNCaP and PC-3 suggest that resveratrol acts through different mechanisms upon the androgen or estrogen receptor cell status.

Non-genomic action of resveratrol on androgen and oestrogen receptors in prostate cancer: modulation of the phosphoinositide 3-kinase pathway

“…This different potency of RES in prostate tumour cells could be related to downregulation of the expression and function of the AR in androgen-responsive LNCaP cells (Mitchell et al, 1999). Our data also support this different sensitivity of prostate tumour cells to RES, as the higher degree of cell death found in LNCaP with respect to PC-3 (Benitez et al, 2007) appears to correlate with a higher inhibition of PI3K activity in the former. Non-nuclear functions have been described for steroid hormone receptors that emphasise their relevance in signalling pathways controlling proliferation and survival.…”

“…However, RES inhibited AR and ERa expression in LNCaP and PC-3 cells, respectively. The antiproliferative activity of RES in these cell lines (Benitez et al, 2007), if mediated through PI3K, would most probably produce a specific inhibition of the steroid receptor-associated PI3K (owing to the anti-oestrogenic potential of this molecule) than a global downregulation of cellular PI3K activity. Regardless the decrease in p85 expression, coimmunoprecipitation experiments revealed that none of the concentrations of RES used compromised AR-or ERa interaction with p85 in LNCaP or PC-3, indicating that inhibition of the steroid-receptor-dependent PI3K activity by RES was not due to changes in AR, ERa or p85 levels.…”

“…The effect of RES on AR-and ERa-dependent signalling was analysed after 36 h of treatment, as no significant apoptosis was observed in short-term (e.g. 30 min) treatments (Benitez et al, 2007). Considering that the interaction between cytosolic steroid receptors (e.g.…”

“…Similar to that observed in ERa-positive MCF-7 breast tumour cells, RES inhibited DNA synthesis and modulated cell cycle progression in androgen receptor (AR)-positive LNCaP but not in AR-negative DU145 human prostate tumour cells (Hsieh and Wu, 1999;Kuwajerwala et al, 2002). Recent studies have also shown that AR status could cause a differential effect of RES on cell cycle regulation at the G1/S transition in LNCaP and PC-3 cells (Benitez et al, 2007). Moreover, RES modulated the transcriptional activity of the AR in LNCaP prostate cancer cells (Mitchell et al, 1999;Gao et al, 2004), inducing changes in gene expression (Narayanan et al, 2003) that were similar to those observed after inhibiting the transcriptional activity of the ERa in MCF-7 breast tumour cells (Pozo-Guisado et al, 2004).…”

E ects of di erent drug treatments on the proliferation of human ovarian carcinoma cell line MDAH-2774

“…It was shown that grape seed extract and resveratrol at concentrations of 1 to 100 µM have varying degrees of cytotoxic and proapoptotic activity in several cancer cell lines (15). Other researchers showed that resveratrol may decrease the proliferation of tumor cells by inducing apoptosis (16)(17)(18).…”