Resveratrol is a class IA phosphoinositide 3-kinase inhibitor

Fröjdö, Sara; Cozzone, D.; Vidal, Hubert; Pirola, Luciano

doi:10.1042/bj20070236

Cited by 144 publications

(61 citation statements)

References 51 publications

(74 reference statements)

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“…2B). This result is also consistent with a recent finding that RSV suppresses PI3K signaling by binding to the ATP-binding site of PI3K (37,39). However, inhibition of Akt did not completely block the inhibitory effect of RSV on mTOR activity (Fig.…”

Section: Discussionsupporting

confidence: 82%

Resveratrol Inhibits mTOR Signaling by Promoting the Interaction between mTOR and DEPTOR

Liu

Wilk

Wang

et al. 2010

Journal of Biological Chemistry

161

130

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Resveratrol (RSV) is a naturally occurring polyphenol that has been found to exert antioxidant, anti-inflammatory, and neuroprotective properties. However, how RSV exerts its beneficial health effects remains largely unknown. Here, we show that RSV inhibits insulin-and leucine-stimulated mTOR signaling in C2C12 fibroblasts via a Sirt1-independent mechanism. Treating C2C12 cells with RSV dramatically inhibited insulin-stimulated Akt, S6 kinase, and 4E-BP1 phosphorylation but had little effect on tyrosine phosphorylation of the insulin receptor and activation of the p44/42 MAPK signaling pathway. RSV treatment also partially blocked mTOR and S6 kinase phosphorylation in TSC1/2-deficient mouse embryonic fibroblasts, suggesting the presence of an inhibitory site downstream of TSC1/2. Knocking out PDK1 or suppressing AMP-activated protein kinase had little effect on leucine-stimulated mTOR signaling. On the other hand, RSV significantly increased the association between mTOR and its inhibitor, DEPTOR. Furthermore, the inhibitory effect of RSV on leucine-stimulated mTOR signaling was greatly reduced in cells in which the expression levels of DEPTOR were suppressed by RNAi. Taken together, our studies reveal that RSV inhibits leucinestimulated mTORC1 activation by promoting mTOR/DEP-TOR interaction and thus uncover a novel mechanism by which RSV negatively regulates mTOR activity. The naturally occurring polyphenol resveratrol (RSV)3 has received great attention during the past few years due to its beneficial roles in longevity, cardioprotection, and immune regulation. How RSV exerts its biological function remains to be fully elucidated, but activation of the NAD ϩ -dependent deacetylase Sirt1 has been suggested as an important mechanism for the life span extension and cancer prevention properties of RSV (1). Several targets of RSV such as AMP-activated protein kinase (AMPK), Akt, and NF-B have also been identified (2-4). However, it remains controversial as to whether activation of these signaling pathways is Sirt1-dependent and whether additional targets and mechanisms are involved in RSV-initiated beneficial function in cells.mTOR (mammalian target of rapamycin) is a member of the phosphatidylinositol 3-kinase (PI3K)-related protein kinase subfamily that plays a critical role in the regulation of various cellular events such as cell growth and proliferation (5, 6). mTOR exists in two distinct complexes, TORC1 and TORC2, which differ in subunit compositions and biological functions (7). The rapamycin-sensitive mTORC1, which consists of five components, including mTOR, Raptor (regulatory-associated protein of mTOR), mLST8 (mammalian lethal with Sec13 protein 8; also known as G␤L), PRAS40 (proline-rich Akt substrate of 40 kDa), and DEPTOR (DEP domain-containing and mTORinteractive protein) (8), regulates protein synthesis and cell growth by phosphorylating downstream target proteins such as p70 ribosomal S6K1 (S6 kinase 1) and the eukaryotic initiation factor 4E-BP1 (5, 9). The rapamycin-insensitive TORC2, which compr...

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Section: Discussionsupporting

confidence: 82%

Resveratrol Inhibits mTOR Signaling by Promoting the Interaction between mTOR and DEPTOR

Liu

Wilk

Wang

et al. 2010

Journal of Biological Chemistry

161

130

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“…In relation to the interaction between insulin signaling pathway and resveratrol, it was shown that resveratrol did not affect expression levels of IRS-1 and IRS-2 [32], consistent with our previous results in the vasculature of male rats [11]. However, resveratrol reduced IRS-1/2 serine/threonine phosphorylations, which are the feedback inhibitors of insulin signaling pathway, and thus promoted the insulin sensitivity [33].…”

Section: Discussionsupporting

confidence: 78%

Long-Term Dietary Fructose Causes Gender-Different Metabolic and Vascular Dysfunction in Rats: Modulatory Effects of Resveratrol

Pektaş¹,

Sadı²,

Akar

2015

Cell Physiol Biochem

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Background/Aims: There is limited knowledge on the gender differences in the effects of dietary fructose. In the current study, we investigated whether long-term fructose intake impacts metabolic parameters and vascular reactivity differently between male and female rats. Moreover, we tested whether resveratrol has a gender-specific effectiveness on the alterations. Methods: Male and female rats were divided into four groups as control; resveratrol; fructose and resveratrol plus fructose. Fructose was given to the rats as 10% solution in drinking water for 24 weeks. All rats were fed with the standard diet with or without resveratrol. Results: High-fructose diet increased plasma insulin, triglyceride and VLDL levels as well as omental weights in both genders. Long-term dietary fructose causes marked increase in body weight of males, but not females. Dietary fructose impaired endothelial relaxation to acetylcholine and intensified contraction to phenylephrine in the aortas of male and female rats, but differently it also reduced insulin-induced vasodilation in aortas of female rats. These changes were associated with decreased expression levels of endothelial nitric oxide synthase (eNOS) mRNA and protein, but increased in inducible NOS (iNOS), in aortas of male and female rats. Dietary fructose suppressed expression levels of sirtuin 1 (SIRT1) and insulin receptor substrate-2 (IRS-2) mRNA in aortas from female rats. Resveratrol supplementation efficiently restored fructose-induced metabolic and vascular dysfunction in both genders probably by regulating eNOS and iNOS production. Moreover, the augmentations in SIRT1 and IRS-2 mRNA in females and IRS-1 mRNA in males may possibly contribute to the beneficial effects of resveratrol as well. Conclusion: Long-term fructose intake may differently affect metabolic and vascular function between male and female rats, which are modified by resveratrol.

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“…activation, Akt, mTOR, p38, and Hsp27 are all induced in response to Cmpd1 (Fig. 6), which is indicative of pleiotropic effects, as has been observed for resveratrol and its metabolites (Yu et al, 2001;Fröjdö et al, 2007;Pirola and Fröjdö, 2008;Pervaiz and Holme, 2009;Calamini et al, 2010). To what extent the combination of these changes facilitates the growth inhibitory effects of Cmpd1 is presently unclear.…”

Section: Discussionmentioning

confidence: 95%

A Resveratrol Analogue Promotes ERK^MAPK–Dependent Stat3 Serine and Tyrosine Phosphorylation Alterations and Antitumor Effects In Vitro against Human Tumor Cells

et al. 2015

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(E )-4-(3,5-dimethoxystyryl)phenyl acetate (Cmpd1) is a resveratrol analog that preferentially inhibits glioma, breast, and pancreatic cancer cell growth, with IC 50 values of 6-19 mM. Notably, the human U251MG glioblastoma tumor line is the most sensitive, with an IC 50 of 6.7 mM, compared with normal fibroblasts, which have an IC 50 . 20 mM. Treatment of U251MG cells that harbor aberrantly active signal transducer and activator of transcription (Stat) 3 with Cmpd1 suppresses Stat3 tyrosine705 phosphorylation in a dose-dependent manner in parallel with the induction of pserine727 Stat3 and extracellular signal-regulated kinase/ mitogen-activated protein kinase 1/2 (pErk1/2 MAPK ). Inhibition of pErk1/2 MAPK induction by the mitogen-activated protein/ extracellular signal-regulated kinase kinase inhibitor PD98059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one] blocked both the pserine727 Stat3 induction and ptyrosine705 Stat3 suppression by Cmpd1, indicating dependency on the mitogen-activated protein/extracellular signal-regulated kinase kinase-Erk1/2 MAPK pathway for Cmpd1-induced modulation of Stat3 signaling. Cmpd1 also blocked epidermal growth factor-stimulated pStat1 induction, whereas upregulating pSrc, pAkt, p-p38, pHeat shock protein 27, and pmammalian target of rapamycin levels. However, pJanus kinase 2 and pEpidermal growth factor receptor levels were not significantly altered. Treatment of U251MG cells with Cmpd1 reduced in vitro colony formation, induced cell cycle arrest in the G2/M phase and cleavage of caspases 3, 8, and 9 and poly(ADP ribose) polymerase, and suppressed survivin, myeloid cell leukemia 1, Bcl-xL, cyclin D1, and cyclin B1 expression. Taken together, these data identify a novel mechanism for the inhibition of Stat3 signaling by a resveratrol analog and suggest that the preferential growth inhibitory effects of Cmp1 occur in part by Erk1/2 MAPK -dependent modulation of constitutively active Stat3.

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Resveratrol is a class IA phosphoinositide 3-kinase inhibitor

Cited by 144 publications

References 51 publications

Resveratrol Inhibits mTOR Signaling by Promoting the Interaction between mTOR and DEPTOR

Resveratrol Inhibits mTOR Signaling by Promoting the Interaction between mTOR and DEPTOR

Long-Term Dietary Fructose Causes Gender-Different Metabolic and Vascular Dysfunction in Rats: Modulatory Effects of Resveratrol

A Resveratrol Analogue Promotes ERK^MAPK–Dependent Stat3 Serine and Tyrosine Phosphorylation Alterations and Antitumor Effects In Vitro against Human Tumor Cells

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Resveratrol is a class IA phosphoinositide 3-kinase inhibitor

Cited by 144 publications

References 51 publications

Resveratrol Inhibits mTOR Signaling by Promoting the Interaction between mTOR and DEPTOR

Resveratrol Inhibits mTOR Signaling by Promoting the Interaction between mTOR and DEPTOR

Long-Term Dietary Fructose Causes Gender-Different Metabolic and Vascular Dysfunction in Rats: Modulatory Effects of Resveratrol

A Resveratrol Analogue Promotes ERKMAPK–Dependent Stat3 Serine and Tyrosine Phosphorylation Alterations and Antitumor Effects In Vitro against Human Tumor Cells

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A Resveratrol Analogue Promotes ERK^MAPK–Dependent Stat3 Serine and Tyrosine Phosphorylation Alterations and Antitumor Effects In Vitro against Human Tumor Cells