Resveratrol, a natural product derived from grape, exhibits antiestrogenic activity and inhibits the growth of human breast cancer cells

Lu, Runqing; Serrero, Ginette

doi:10.1002/(sici)1097-4652(199906)179:3<297::aid-jcp7>3.0.co;2-p

Cited by 306 publications

(188 citation statements)

References 45 publications

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“…MCF-7 cells were cultured in a 1:1 mixture of DMEM and Ham's F-12 medium supplemented with 5% (vol͞vol) FBS. One day before the start of the experiment, the medium was changed to E 2 -depleted PFMEM (phenol red-free ␣-MEM) supplemented with 5% charcoal-extracted FBS as described (15). Twenty-four hours later, the medium was replaced with PFMEM.…”

supporting

confidence: 59%

Mediation of estrogen mitogenic effect in human breast cancer MCF-7 cells by PC-cell-derived growth factor (PCDGF/granulin precursor)

Lu¹

2000

Proceedings of the National Academy of Sciences

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PC-cell-derived growth factor (PCDGF) is an 88-kDa glycoprotein corresponding to the granulin precursor. We have reported that PCDGF was expressed in human breast cancer cells. In estrogenreceptor positive cells, 17-␤-estradiol (E2) transcriptionally stimulated PCDGF expression in a dose-and time-dependent fashion. We demonstrate here that PCDGF mediates the mitogenic effect of E 2 in MCF-7 cells. PCDGF substituted for E2 to stimulate DNA synthesis. The E 2 mitogenic effect was inhibited in a dose-dependent fashion by anti-PCDGF neutralizing antibody. Inhibition of PCDGF expression by antisense transfection also inhibited the E 2 mitogenic effect. In contrast, overexpression of PCDGF in MCF-7 cells resulted in cells that were able to proliferate in the absence of estrogen and were tamoxifen resistant. The PCDGF signaling pathway was examined. Like E2, PCDGF stimulated mitogen-activated protein kinase activity. PCDGF could substitute for E 2 in stimulating cyclin D1 expression. The cyclin D1 stimulation by E 2 was 50% inhibited by anti-PCDGF antibody. In contrast, PCDGF did not stimulate c-myc expression, another molecular target of E2. We conclude that autocrine PCDGF mediates the E 2 mitogenic effect via stimulation of cyclin D1. These studies provide information on estrogen action and identify an autocrine molecular target in human breast cancer cells.

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supporting

confidence: 59%

Mediation of estrogen mitogenic effect in human breast cancer MCF-7 cells by PC-cell-derived growth factor (PCDGF/granulin precursor)

Lu¹

2000

Proceedings of the National Academy of Sciences

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“…In relation to this, others have also shown that resveratrol exhibits various degrees of estrogenic effects (Gehm et al 1997). However, there are other more recent investigations that question whether resveratrol has any significant estrogenic activity at all, so this issue is still open to some debate (Ashby et al 1999, Lu & Serrero 1999, Turner et al 1999) and warrants further investigation. Furthermore, as shown in models similar to the SBMC model, prostaglandins may inhibit osteogenesis (Ogiso et al 1992).…”

Section: Differentiationmentioning

confidence: 99%

Inhibition of dioxin effects on bone formation in vitro by a newly described aryl hydrocarbon receptor antagonist, resveratrol

Singh¹,

Casper²,

Fritz³

et al. 2000

Journal of Endocrinology

131

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Aryl hydrocarbon receptor (AhR) ligands are environmental contaminants found in cigarette smoke and other sources of air pollution. The prototypical compound is TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), also known as dioxin. There is an increasing body of knowledge linking cigarette smoking to osteoporosis and periodontal disease, but the direct effects of smokeassociated aryl hydrocarbons on bone are not well understood. Through the use of resveratrol (3,5,4 -trihydroxystilbene), a plant antifungal compound that we have recently demonstrated to be a pure AhR antagonist, we have investigated the effects of TCDD on osteogenesis. It was postulated that TCDD would inhibit osteogenesis in bone-forming cultures and that this inhibition would be antagonized by resveratrol. We employed the chicken periosteal osteogenesis (CPO) model, which has been shown to form bone in vitro in a pattern morphologically and biochemically similar to that seen in vivo, as well as a rat stromal cell bone nodule formation model. In the CPO model, alkaline phosphatase (AP) activity was reduced by up to 50% (P<0·01 vs control) in the presence of 10 9 M TCDD and these effects were reversed by 10 6 M resveratrol (P<0·05 vs TCDD alone). TCDD-mediated inhibition of osteogenesis was restricted primarily to the osteoblastic differentiation phase (days 0-2) as later addition did not appear to have any effects. Message levels for important bone-associated proteins (in the CPO model) such as collagen type I, osteopontin, bone sialoprotein and AP were inhibited by TCDD, an effect that was antagonized by resveratrol. Similar findings were obtained using the rat stromal bone cell line. TCDD (at concentrations as low as 10 10 M) caused an approximately 33% reduction in AP activity, which was abrogated by 3·5 10 7 M resveratrol. TCDD also induced a marked reduction in mineralization (75%) which was completely antagonized by resveratrol. These data suggest that AhR ligands inhibit osteogenesis probably through inhibition of osteodifferentiation and that this effect can be antagonized by resveratrol. Since high levels of AhR ligands are found in cigarette smoke, and further since smoking is an important risk factor in both osteoporosis and periodontal disease, it may be postulated that AhR ligands are the component of cigarette smoke linking smoking to osteoporosis and periodontal disease. If so, resveratrol could prove to be a promising preventive or therapeutic agent for smoking-related bone loss.

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“…Indeed, it was reported that resveratrol acts as an estrogen agonist 42 ± 44 or antagonist 45 and binds to the estrogen receptor. 46 Thus, we cannot rule out the involvement of a putative receptor in the apoptosisinducing effect of resveratrol.…”

Section: Cell Death and Differentiationmentioning

confidence: 99%

Resveratrol causes arrest in the S-phase prior to Fas-independent apoptosis in CEM-C7H2 acute leukemia cells

et al. 2000

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Resveratrol (3,5,4'-trihydroxy-trans-stilbene), in the concentration range of 20 mM and above, induced arrest in the Sphase and apoptosis in the T cell-derived T-ALL lymphocytic leukemia cell line CEM-C7H2 which is deficient in functional p53 and p16. Expression of transgenic p16/INK4A, which causes arrest in G0/G1, markedly reduced the percentage of apoptotic cells. Antagonist antibodies to Fas or FasL, or constitutive expression of crmA did not diminish the extent of resveratrol-induced apoptosis. Furthermore, a caspase-8-negative, Fas-resistant Jurkat cell line was sensitive to resveratrol-induced apoptosis which could be strongly inhibited in the Jurkat as well as in the CEM cell line by z-VAD-fmk and z-IETD-fmk. The almost complete inhibition by z-IETD-fmk and the lack of inhibition by crmA suggested caspase-6 to be the essential initiator caspase. Western blots revealed the massive conversion of procaspase-6 to its active form, while caspase-3 and caspase-2 were proteolytically activated to a much lesser extent. Cell Death and Differentiation (2000) 7, 834 ± 842.

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Resveratrol, a natural product derived from grape, exhibits antiestrogenic activity and inhibits the growth of human breast cancer cells

Cited by 306 publications

References 45 publications

Mediation of estrogen mitogenic effect in human breast cancer MCF-7 cells by PC-cell-derived growth factor (PCDGF/granulin precursor)

Mediation of estrogen mitogenic effect in human breast cancer MCF-7 cells by PC-cell-derived growth factor (PCDGF/granulin precursor)

Inhibition of dioxin effects on bone formation in vitro by a newly described aryl hydrocarbon receptor antagonist, resveratrol

Resveratrol causes arrest in the S-phase prior to Fas-independent apoptosis in CEM-C7H2 acute leukemia cells

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