The anticancer effects of curcumin via targeting the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway

摘要

The mammalian target of rapamycin (mTOR) is a protein kinase that has been considered as a key regulator of a large number of cellular processes, including cell growth, proliferation, differentiation, survival, and motility. Overactivation of mTOR (especially mTORC1) signaling is related to oncogenic cellular processes. Therefore targeting mTORC1 signaling is a new promising strategy in cancer therapy. In this regard, various studies have shown that curcumin, a polyphenol produced from the turmeric rhizome, has anti-inflammatory, antioxidant and anticancer properties. Curcumin may exert its anticancer function, at least in part, by suppressing mTOR-mediated signaling pathway in tumor cells. However, the exact underlying mechanisms by which curcumin blocks the mTORC1 signaling remain unclear. According to literature, curcumin inhibits insulin-like growth factor 1 (IGF-1)/phosphoinositide 3-kinase (PI3K)/Akt/mTORC1 pathway which leads to apoptosis and cell cycle arrest via suppression of erythroblastosis virus transcription factor 2 and murine double minute 2 oncoprotein. In addition, activation of unc-51-like kinase 1 by curcumin, as a downstream target of IGF-1/PI3K/Akt/mTORC1 axis, enhances autophagy. Curcumin induces AMP-activated protein kinase, a negative regulator of mTORC1, via inhibition of F0F1-ATPase. Interestingly, curcumin suppresses I kappa B kinase beta, the upstream kinase in mTORC1 pathway. Moreover, evidence revealed that curcumin downregulates the E3-ubiquitin ligases NEDD4, neural precursor cell-expressed developmentally downregulated 4. NEDD4 is frequently overexpressed in a wide range of cancers and degrades the phosphatase and tensin homolog, which is a negative regulator of mTORC1. Finally another suggested mechanism is suppression of MAOA/mTORC1/hypoxia-inducible factor 1 alpha signaling pathway by curcumin.