Abstract
Ursolic acid (UA), a pentacyclic triterpenoid widely found in medicinal herbs and fruits, has been reported to possess a wide range of beneficial properties including anti-hyperglycemia, anti-obesity, and anti-cancer. However, the molecular mechanisms underlying the action of UA remain largely unknown. Here we show that UA inhibits leucine-induced activation of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway in C2C12 myotubes. The UA-mediated inhibition of mTORC1 is independent of Akt, tuberous sclerosis complex 1/2 (TSC1/2), and Ras homolog enriched in brain (Rheb), suggesting that UA negatively regulates mTORC1 signaling by targeting at a site downstream of these mTOR regulators. UA treatment had no effect on the interaction between mTOR and its activator Raptor or inhibitor Deptor, but suppressed the binding of RagB to Raptor and inhibited leucine-induced mTOR lysosomal localization. Taken together, our study identifies UA as a direct negative regulator of the mTORC1 signaling pathway and suggests a novel mechanism by which UA exerts its beneficial function.
Highlights
Ursolic acid (UA) is a triterpene compound derived from certain traditional medicinal plants [1]
We investigated the effect of UA on mechanistic target of rapamycin (mTOR) signaling, we found that UA inhibits leucine-stimulated mTOR activation in C2C12 myotubes by inhibiting mTOR from targeting to lysosome, uncovering a novel mechanism underlying the negative regulation of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway by UA, a small molecule that possess a wide range of beneficial properties including anti-hyperglycemia, anti-obesity, and anticancer
Several recent studies show that UA exerts its anti-tumor role through inhibition of the mTOR signaling pathway [39], suggesting a potential mechanism underlying the beneficial effects of UA
Summary
Ursolic acid (UA) is a triterpene compound derived from certain traditional medicinal plants [1]. UA has been found to possess a wide range of health benefits such as anti-obesity-related diseases [2], anti-hyperglycemia [3] and anti-cancer [4]. The molecular mechanisms underlying the beneficial effects of UA remain largely unknown. UA has been shown to ameliorate hepatic fibrosis by decreasing Akt phosphorylation and blocking NFkB nuclear localization in mouse hepatocytes [5]. UA has been found to inhibit the initiation and progression of prostate cancer by down-regulation of various proinflammatory mediators including NF-kB, STAT3, Akt and IKKa/b [6]. Whether UA has additional targets remains to be determined
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