Abstract
The mechanistic/mammalian target of rapamycin (mTOR) pathway plays a critical role in cellular metabolism, growth, and proliferation and has been evaluated as a target for therapy in various malignancies. The mTOR pathway is a major tumor-initiating pathway in hepatocellular carcinoma, with up-regulation seen in up to 50% of tumors. Metformin, which represses mTOR signaling by activating adenosine monophosphate-activated protein kinase, has been shown to decrease liver carcinogenesis in population studies. mTOR inhibitors such as everolimus have been evaluated as adjunctive chemotherapy with some success, although efficacy has been limited by the lack of complete mTOR pathway inhibition. The active site mTOR inhibitors hold greater promise, given that they offer complete mTOR suppression. There is also evidence of mTOR pathway activation in cholangiocarcinoma, although its biological significance in initiating and promoting tumor progression remains ambiguous. This review provides an overview of the complex biochemistry behind the mTOR pathway and its role in carcinogenesis, especially as it pertains to hepatic malignancies.
Highlights
The mTOR Pathway in Hepatic MalignanciesThe mechanistic/mammalian target of rapamycin (mTOR) pathway plays a critical role in cellular metabolism, growth, and proliferation and has been evaluated as a target for therapy in various malignancies
The mechanistic/mammalian target of rapamycin pathway plays a critical role in cellular metabolism, growth, and proliferation and has been evaluated as a target for therapy in various malignancies
References to mammalian target of rapamycin (mTOR) in the literature predominantly pertain to the activity of mTOR complex 1 (mTORC1), which is sensitive to sirolimus. mTORC1 associates with at least four other proteins: mammalian lethal with SEC13 protein 8, regulatory-associated protein of mTOR (Raptor), proline-rich AKT substrate of 40 kDa (PRAS40), and DEP domain—containing mTOR-interacting protein (Deptor)
Summary
The mechanistic/mammalian target of rapamycin (mTOR) pathway plays a critical role in cellular metabolism, growth, and proliferation and has been evaluated as a target for therapy in various malignancies. Metformin, which represses mTOR signaling by activating adenosine monophosphate–activated protein kinase, has been shown to decrease liver carcinogenesis in population studies. MTOR inhibitors such as everolimus have been evaluated as adjunctive chemotherapy with some success, efficacy has been limited by the lack of complete mTOR pathway inhibition. The active site mTOR inhibitors hold greater promise, given that they offer complete mTOR suppression. There is evidence of mTOR pathway activation in cholangiocarcinoma, its biological significance in initiating and promoting tumor progression remains ambiguous. This review provides an overview of the complex biochemistry behind the mTOR pathway and its role in carcinogenesis, especially as it pertains to hepatic malignancies. This review provides an overview of the complex biochemistry behind the mTOR pathway and its role in carcinogenesis, especially as it pertains to hepatic malignancies. (HEPATOLOGY 2013;58:810-818)
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