Resveratrol inhibits mTOR signaling by targeting DEPTOR

Abstract

Resveratrol (RSV, trans-3, 4, 5-Trihydroxystilbene), a type of polyphenol originally found in red wines, shows a great promise for the treatment of cancer, aging, type 2 diabetes, and cardiovascular diseases. Recent studies suggest that suppressing the signaling pathway mediated by mTOR, a well-known energy sensor that integrates various hormonal, nutrient, and environmental signals to regulate cell growth, metabolism and survival, could play an important role in mediating the beneficial effect of RSV. The underlying mechanisms by which RSV inhibits mTOR signaling remain elusive, but our recent studies show that RSV inhibits amino acid-stimulated mTOR signaling in C2C12 fibroblasts via a Sirt1- and AMPK-independent mechanism. RSV treatment has no effect on the expression levels of mTOR, raptor and DEPTOR, but greatly promotes the interaction between mTOR and its inhibitor DEPTOR. Our results reveal a novel mechanism by which RSV inhibits mTOR signaling and its function.

Acknowledgments

This work is supported by National Institutes of Health Grants RO1 DK76902 (to F.L.).

Figures and Tables

Figure 1 Mechanisms by which RSV inhibits insulin and amino acid-induced mTOR activation. (1) RSV binds to the ATP-binding site of the p110 subunit of PI3K and competitively inhibits the binding of ATP to the enzyme, leading to suppression of mTOR activity and downstream signaling. (2) RSV promotes the interaction between mTOR and its inhibitor DEPTOR, resulting in an inhibition of mTOR signaling.