Resveratrol induces growth inhibition and apoptosis in metastatic breast cancer cells via de novo ceramide signaling

Abstract

Resveratrol (3,4',5-trans-trihydroxystilbene), a phytoalexin present in grapes and red wine, is emerging as a natural compound with potential anticancer properties. Here we show that resveratrol can induce growth inhibition and apoptosis in MDA-MB-231, a highly invasive and metastatic breast cancer cell line, in concomitance with a dramatic endogenous increase of growth inhibitory/proapoptotic ceramide. We found that accumulation of ceramide derives from both de novo ceramide synthesis and sphingomyelin hydrolysis. More specifically we demonstrated that ceramide accumulation induced by resveratrol can be traced to the activation of serine palmitoyltransferase (SPT), the key enzyme of de novo ceramide biosynthetic pathway, and neutral sphingomyelinase (nSMase), a main enzyme involved in the sphingomyelin/ceramide pathway. However, by using specific inhibitors of SPT, myriocin and L-cycloserine, and nSMase, gluthatione and manumycin, we found that only the SPT inhibitors could counteract the biological effects induced by resveratrol. Thus, resveratrol seems to exert its growth inhibitory/apoptotic effect on the metastatic breast cancer cell line MDA-MB-231 by activating the de novo ceramide synthesis pathway.

Caspase-2 Triggers Bax-Bak-dependent and -independent Cell Death in Colon Cancer Cells Treated with Resveratrol

“…Resveratrol has been reported to induce caspase activation subsequent to mitochondrial release of cytochrome c (2,4,21), caspase activation independent of cytochrome c release (25), caspase-8-mediated Bax/Bak-dependent cell death (28), p53-or Bax-dependent and -independent cell death (26), ceramide-mediated cell cycle arrest and apoptosis (42), and death receptor (CD95)-dependent death signaling (38). Multiple and diverging death signaling events, all converging to apoptosis in different cells, suggest that resveratrol-induced cell death varies from cell to cell, indicating a possible role for regulatory molecules of apoptosis that govern the apoptotic threshold of a cell.…”

“…Ceramide, etoposide, and other genotoxic agents are known to be the inducers of caspase-2 (52). Ceramide generation with resveratrol reported in MADA-MB-231 breast cancer cells may also be a possible trigger for caspase-2 activation (42).…”

Resveratrol-induced cyclooxygenase-2 facilitates p53-dependent apoptosis in human breast cancer cells

“…Treatment of human mammary epithelial cells with C 2 -ceramide increases levels of COX-2 protein and mRNA and enhances prostaglandin E 2 synthesis (42). Recently, other studies have shown that resveratrol induces apoptosis through a ceramide signal transduction pathway (43,44). It is therefore reasonable to speculate that the induction by resveratrol of COX-2 -dependent apoptosis requires ceramide signaling.…”

Role of non-canonical Beclin 1-independent autophagy in cell death induced by resveratrol in human breast cancer cells

“…Many cancer chemotherapies and radiation are potent inducers of autophagy. 5 Resveratrol (Res), a polyphenol found in grapes, peanuts and other plants, has potent antioxidant and antitumorigenic activities, 6 affects tumor initiation and promotion, and arrests angiogenesis and metastasis. It is also able to stimulate apoptosis, arrest cell cycle and suppress kinase pathways.…”