Resveratrol-induced Apoptosis Is Associated with Fas Redistribution in the Rafts and the Formation of a Death-inducing Signaling Complex in Colon Cancer Cells

Delmas, Dominique; Rébé, Cédric; Lacour, Sandrine; Filomenko, Rodolphe; Athias, Anne; Gambert, Philippe; Cherkaoui-Malki, Mustapha; Jannin, Brigitte; Dubrez, Laurence; Latruffe, Norbert; Solary, Éric

doi:10.1074/jbc.m304896200

Cited by 260 publications

(208 citation statements)

References 50 publications

(39 reference statements)

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“…Several studies have shown that RES can induce apoptosis by an alternative pathway mediated by caspase-8. 59,60 However, RES did not induce caspase-8 activity in MCF-7 cells, further supporting the hypothesis that apoptosis in this cell line was not caspase-mediated. Downstream apoptotic events regulated by caspase activity, such as PARP proteolysis and nucleosomal DNA laddering, were also absent in MCF-7, again suggesting that apoptosis induction by RES in these cells should follow an alternative, non-caspase-mediated mechanism.…”

Section: Discussionsupporting

confidence: 66%

Resveratrol‐induced apoptosis in MCF‐7 human breast cancer cells involves a caspase‐independent mechanism with downregulation of Bcl‐2 and NF‐κB

Pozo‐Guisado

Merino

Mulero‐Navarro

et al. 2005

Intl Journal of Cancer

205

143

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Resveratrol (RES), a chemopreventive molecule, inhibits the proliferation of tumor cells of different etiologies. We previously showed that RES alters the cell cycle and induces apoptosis in MCF-7 breast tumor cells by interfering with the estrogen receptor (ERa)-dependent phosphoinositide 3-kinase (PI3K) pathway. Here, we analyzed signaling downstream of PI3K, to understand the mechanisms of RES-induced apoptosis. Apoptotic death by RES in MCF-7 was mediated by Bcl-2 downregulation since overexpression of this protein abolished apoptosis. Decreased Bcl-2 levels were not related to cytochrome c release, activation of caspases 3/8 or poly(ADP-ribose) polymerase proteolysis. However, RES decreased mitochondrial membrane potential and increased reactive oxygen species and nitric oxide production. NF-kB, a regulator of Bcl-2 expression, and calpain protease activity, a regulator of NF-kB, were both inhibited by RES. The patterns for NFkB and calpain activities followed that of PI3K and were inhibited by LY294002. NF-kB inhibition coincided with diminished MMP-9 activity and cell migration. These data suggest that RES-induced apoptosis in MCF-7 could involve an oxidative, caspase-independent mechanism, whereby inhibition of PI3K signaling converges to Bcl-2 through NF-kB and calpain protease activity. Therefore, Bcl-2 and NF-kB could be considered potential targets for the chemopreventive activity of RES in estrogen-responsive tumor cells. ' 2005 Wiley-Liss, Inc.Key words: resveratrol; caspase; Bcl-2; NF-kB; apoptosis Among natural compounds with beneficial effects on human health, RES (3,4 0 ,5-trihydroxystilbene) has attracted considerable interest. This molecule, present at relevant concentrations in red wine, 1 has been associated with a lower incidence of cardiovascular disease. Different studies have also suggested a beneficial effect of RES in cancer since it inhibits proliferation and promotes death in tumor cell lines of different origins, 2-4 and, in vivo, suppresses the formation of skin 5 and mammary gland 6 tumors in rodent models of carcinogenesis.We, as well as other laboratories, have found that the ability of RES to inhibit cell viability and proliferation in the human breast cancer cell lines MCF-7 and MDA-MB-231 was unrelated to ERa status. 7,8 However, apoptotic cell death was present only in ERapositive MCF-7 and involved cell-specific regulation of the G 1 /S and G 2 /M transitions of the cell cycle. 2,8 RES properties are related to ERa since this compound has estrogenic or antiestrogenic activities depending on its concentration and the phenotype of the target cell. 9,10 ERa, in addition to its nuclear role as a transcription factor, is involved in regulating the PI3K pathway, which controls cell growth, proliferation and apoptosis. [11][12][13] In MCF-7 cells, RES induced a biphasic pattern of PI3K activity that increased at low concentrations and decreased at high concentrations. Activation of downstream PI3K effectors PKB/AKT and GSK-3 closely followed the pattern of PI3K activity. 14 The ...

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Section: Discussionsupporting

confidence: 66%

Resveratrol‐induced apoptosis in MCF‐7 human breast cancer cells involves a caspase‐independent mechanism with downregulation of Bcl‐2 and NF‐κB

Pozo‐Guisado

Merino

Mulero‐Navarro

et al. 2005

Intl Journal of Cancer

205

143

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“…Caspase-10 activation in taxol-induced apoptosis was proposed to involve the adapter molecule FADD independently of death receptors (Park et al, 2004). We and other have demonstrated that a ligandindependent, death receptor-mediated pathway could contribute to cytotoxic drug-induced apoptosis (Micheau et al, 1999;Lacour et al, 2001;Delmas et al, 2003). Here, we show that constructs that interfere with the extrinsic pathway to apoptosis such as a dominant-negative FADD mutant (Chinnaiyan et al, 1996) and the viral protein MC159 (Bertin et al, 1997) Caspase-10 in drug-induced apoptosis R Filomenko et al do not prevent nor delay caspase-10 activation in response to etoposide, suggesting that the death receptor pathway is not involved in the studied pathway.…”

Section: Discussionmentioning

confidence: 97%

Caspase-10 involvement in cytotoxic drug-induced apoptosis of tumor cells

et al. 2006

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“…In in vitro studies, Res has inhibited cell proliferation and exerted direct effects on cytotoxicity by induction of apoptosis in various tumor cell lines, including melanoma, 4 lung cancer, 5 myeloid leukemia, 25 breast cancer, 7,26 medulloblastoma 6 and colon 27 cancer cells. In vivo supplementation with Res was shown to protect animals from transplanted parental tumors or from tumorigenesis induced by carcinogens.…”

Section: Discussionmentioning

confidence: 99%

Effect of resveratrol on the development of spontaneous mammary tumors in HER‐2/neu transgenic mice

Provinciali

Donnini

et al. 2005

Intl Journal of Cancer

113

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Resveratrol (Res) has been reported to possess cancer chemopreventive activity on the basis of its in vitro effects on tumor cells and in vivo experimental models of rodents transplanted with parental tumors or treated with carcinogens. We investigated the effects of Res on the development of mammary tumors appearing spontaneously in HER-2/neu transgenic mice at an early age. The mechanisms involved in the Res antitumor effect were evaluated by studying the immune effectiveness, tumor apoptosis and expression of mRNA and protein for HER-2/neu in tumoral mammary glands from Res-treated mice and in tumor cell lines. Res supplementation delayed the development of spontaneous mammary tumors (p < 0.001), reduced the mean number and size of mammary tumors (p < 0.0001) and diminished the number of lung metastases in HER-2/neu transgenic mice. The effects of Res were associated with downregulation of HER-2/neu gene expression and increased apoptosis both in tumoral mammary glands and in murine (N202) and human (SKBr3) tumor cell lines. Neither the basal, the IL-2-induced NK activity nor the lymphocyte number and proliferation was modified in Res-supplemented compared to control mice. Our results demonstrate that Res supplementation delays the development and reduces the metastasizing capacity of spontaneous mammary tumors in HER-2/neu transgenic mice. The antitumor effect of Res might be related to the downregulation of HER-2/neu expression and the induction of apoptosis in tumor cells. ' 2005 Wiley-Liss, Inc.Key words: resveratrol; HER-2/neu; mammary tumor; transgenic mouse; apoptosis Cancer chemoprevention, the prevention of cancer by chemical agents that reduce the risk of carcinogenesis, is one of the most direct ways to reduce morbidity and mortality. Res (trans-3,4 0 , 5-trihydroxystilbene) is a naturally occurring polyphenolic antioxidant compound present in grapes, mulberries, peanuts and red wine. It has been identified as an excellent candidate cancer chemopreventive, based on its safety and efficacy in experimental models of carcinogenesis. It has been found to inhibit diverse cellular events associated with tumor initiation, promotion and progression. 1 Most of the antitumor activity of Res has been discovered through in vitro studies in tumor cell lines. In these studies, Res was generally found to induce growth inhibition and apoptosis of a panel of human and murine tumor cell lines. [2][3][4][5][6][7] Fewer studies have been conducted on the antitumor effect exerted by in vivo supplementation with Res. Res was found to inhibit tumorigenesis in a mouse skin cancer model. 1 In other studies, it protected rats from ascites hepatoma 8 and colon carcinogenesis 9 and exerted inhibitory effects on tumor growth and lung metastasis in mice bearing highly metastatic Lewis lung carcinoma. 10 In the latter study, the effect of Res was related to its proapoptotic and antiangiogenic action on tumor cells, with no evidence of modulation of the immune response. 10 Res also inhibited the growth of experimentally implante...

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Resveratrol-induced Apoptosis Is Associated with Fas Redistribution in the Rafts and the Formation of a Death-inducing Signaling Complex in Colon Cancer Cells

Cited by 260 publications

References 50 publications

Resveratrol‐induced apoptosis in MCF‐7 human breast cancer cells involves a caspase‐independent mechanism with downregulation of Bcl‐2 and NF‐κB

Resveratrol‐induced apoptosis in MCF‐7 human breast cancer cells involves a caspase‐independent mechanism with downregulation of Bcl‐2 and NF‐κB

Caspase-10 involvement in cytotoxic drug-induced apoptosis of tumor cells

Effect of resveratrol on the development of spontaneous mammary tumors in HER‐2/neu transgenic mice

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