Hitting the TORget: curcumin disrupts mTORC1 and mTORC2

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Previous studies have demonstrated that the polyphenol natural product curcumin potently inhibits the mTOR complex 1 (mTORC1)-mediated phosphorylation of S6K1 and 4E-BP1 and the mTOR complex 2 (mTORC2)-mediated phosphorylation of Akt in muscle, prostate, breast, cervical, and colon cancer cell lines, and also induces sustained phosphorylation of c-Jun. This study is designed to elucidate the underlying mechanisms of curcumin for these cellular effects. We observed that curcumin disrupted mTOR signaling in a PP2A-independent manner, as curcumin was able to inhibit phosphorylation of S6K1, 4E-BP1, and Akt in the presence of both the PP2A inhibitor okadaic acid and a dominant-negative form of PP2A. Curcumin also dose-dependently stimulated the demethylation of PP2A, an event associated with PP2A inactivation. Furthermore, we investigated whether curcumin inhibits mTOR signaling through a TSC2-dependent manner, and found that curcumin had no effect on TSC1/TSC2 interaction, but only prevented/activated phosphorylation of TSC2 and AMPKα at concentrations well above those at which mTOR signaling was inhibited. We discovered, however, that curcumin directly inhibited the kinase activity of both mTOR complexes in a dose-dependent manner by disrupting the association of mTOR with raptor in the mTORC1 and the association of mTOR with rictor in the mTORC2. We also observed that curcumin prevented the phosphatidic acid-stimulated phosphorylation of S6K1 and 4E-BP1, suggesting that curcumin might bind directly to mTOR at the same domain (FRB) as rapamycin. Finally, we noticed that curcumin induced hyperphosphorylation of c-Jun through the ASK1 cascade, as curcumin treatment led to activation of ASK1, MKK4, and JNK.