Resveratrol inhibits Src and Stat3 signaling and induces the apoptosis of malignant cells containing activated Stat3 protein

Kotha, Anupama; Sekharam, Madhavi; Cilenti, Lucia; Siddiquee, Khandaker; Khaled, Annette R.; Zervos, Antonis S.; Carter, Bradford; Turkson, James; Jove, Richard

doi:10.1158/1535-7163.mct-05-0268

Cited by 263 publications

(197 citation statements)

References 58 publications

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“…We used resveratrol to provide support that targeting STAT3 acetylation with small-molecule drugs can reverse aberrant CpG island methylation at several tumor-suppressor gene promoters in cancer cells. Although resveratrol is regarded as an inhibitor of acetylation (27), it was discovered to be a STAT3 inhibitor (34). Reveratrol was later shown to inhibit STAT3 acetylation (28), which is confirmed by our data.…”

Section: Discussionsupporting

confidence: 88%

Acetylated STAT3 is crucial for methylation of tumor-suppressor gene promoters and inhibition by resveratrol results in demethylation

Lee

Zhang

Herrmann

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The mechanisms underlying hypermethylation of tumor-suppressor gene promoters in cancer is not well understood. Here, we report that lysine acetylation of the oncogenic transcription factor STAT3 is elevated in tumors. We also show that genetically altering STAT3 at Lys685 reduces tumor growth, which is accompanied by demethylation and reactivation of several tumor-suppressor genes. Moreover, mutating STAT3 at Lys685 disrupts DNA methyltransferase 1-STAT3 interactions in cultured tumor cells and in tumors. These observations are confirmed by treatment with an acetylation inhibitor, resveratrol. Furthermore, reduction of acetylated STAT3 in triple-negative breast cancer cells leads to demethylation and activation of the estrogen receptor-α gene, sensitizing the tumor cells to antiestrogens. Our results also demonstrate a correlation between STAT3 acetylation and methylation of estrogen receptor-α in melanoma, which predicts melanoma progression. Taken together, these results suggest a role of STAT3 acetylation in regulating CpG island methylation, which may partially explain aberrant gene silencing in cancer. These findings also provide a rationale for targeting acetylated STAT3 for chemoprevention and cancer therapy.

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Section: Discussionsupporting

confidence: 88%

Acetylated STAT3 is crucial for methylation of tumor-suppressor gene promoters and inhibition by resveratrol results in demethylation

Lee

Zhang

Herrmann

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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200

202

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“…PANC-1 is a pancreatic epitheloid carcinoma with high levels of endogenous pSTAT3, whereas both BXPC-3 and HPAC are adenocarcinoma cell lines with elevated levels of pSTAT3 (23,24). In accordance with our observations in MDA-MB-231, GO-Y030 was again the more potent of the two compounds in each of the pancreatic cell lines evaluated (Table I).…”

Section: Go-y030 Is a More Potent Inhibitor Of Viability In Human Bresupporting

confidence: 87%

Curcumin analogue GO-Y030 inhibits STAT3 activity and cell growth in breast and pancreatic carcinomas

Hutzen

Friedman²,

Sobo³

et al. 2009

Int J Oncol

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Abstract. Curcumin has numerous anti-carcinogenic properties, but low bioavailability prevents its use in chemotherapeutic applications. One strategy for circumventing this problem has been the creation of synthetic analogues. We tested the efficacy of an analogue known as GO-Y030 in human breast and pancreatic cancer cells. We compared the impact of curcumin and GO-Y030 on the breast cancer cell line MDA-MB-231 and pancreatic cancer cell lines, PANC-1, HPAC and BXPC-3. Both compounds reduced cell viability and induced apoptosis, but GO-Y030 was substantially more potent. We also demonstrated that GO-Y030 was capable of interfering with STAT3, a persistently activated transcription factor in many cancer types. GO-Y030 inhibited STAT3 phosphorylation and transcriptional activity whereas comparable dosages of curcumin had little or no effect. These results indicate that GO-Y030 is a potent inhibitor of cell viability and STAT3 activation, and may thus have potential as a therapeutic agent for cancers expressing high levels of activated STAT3.

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“…Resveratrol (RSV) was previously shown to suppress JAK2-STAT3, Src-STAT3 and IKK-NF-κB activation and to induce apoptosis in some cancer cell lines [16][17][18]. We have demonstrated that, as with sodium arsenite, RSV suppressed expression of antiapoptotic cFLIP protein in human melanomas and dramatically increased sensitivity to exogenous TRAIL in TRAIL-R2/DR5-positive melanomas.…”

Section: Introductionmentioning

confidence: 99%

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

Ivanov

Partridge

Johnson

et al. 2008

Experimental Cell Research

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Although many human melanomas express the death receptors TRAIL-R2/DR5 or TRAIL-R1/ DR4 on cell surface, they often exhibit resistance to exogenous TRAIL. One of the main contributors to TRAIL-resistance of melanoma cells is upregulation of transcription factors STAT3 and NF-κB that control the expression of antiapoptotic genes, including cFLIP and BclxL. On the other hand, the JNK-cJun pathway is involved in the negative regulation of cFLIP (a caspase-8 inhibitor) expression. Our observations indicated that resveratrol, a polyphenolic phytoalexin, decreased STAT3 and NF-κB activation, while activating JNK-cJun that finally suppressed expression of cFLIP and Bcl-xL proteins and increased sensitivity to exogenous TRAIL in DR5-positive melanomas. Interestingly, resveratrol did not increase surface expression of DR5 in human melanomas, while γ-irradiation or sodium arsenite treatment substantially upregulated DR5 expression. Hence, an initial increase in DR5 surface expression (either by γ-irradiation or arsenite), and subsequent downregulation of antiapoptotic cFLIP and Bcl-xL (by resveratrol), appear to constitute an efficient approach to reactivate apoptotic death pathways in TRAIL-resistant human melanomas. In spite of partial suppression of mitochondrial function and the mitochondrial death pathway, melanoma cells still retain the potential to undergo the DR5-mediated, caspase-8-dependent death pathway that could be accelerated by either an increase in DR5 surface expression or suppression of cFLIP. Taken together, these results suggest that resveratrol, in combination with TRAIL, may have a significant efficacy in the treatment of human melanomas.

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Resveratrol inhibits Src and Stat3 signaling and induces the apoptosis of malignant cells containing activated Stat3 protein

Cited by 263 publications

References 58 publications

Acetylated STAT3 is crucial for methylation of tumor-suppressor gene promoters and inhibition by resveratrol results in demethylation

Acetylated STAT3 is crucial for methylation of tumor-suppressor gene promoters and inhibition by resveratrol results in demethylation

Curcumin analogue GO-Y030 inhibits STAT3 activity and cell growth in breast and pancreatic carcinomas

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

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