Combinational therapy targeting the MET-mTOR-ROS loop disrupts mitochondrial autoregulatory machinery of liver cancer.

ABSTRACT: A wide variety of regulators have been identified in mechanistic target of rapamycin (mTOR) activation; however, the protective mechanisms of mTOR inactivation are still largely unknown, especially in tumor growth. Here, we have found the hepatocyte growth factor (HGF) receptor (MET) is required for mTOR activation-stimulated mitochondrial oxidative phosphorylation (OXPHOS) in a phosphorylation-dependent manner in liver cancer. Intriguingly, we observed mitochondrial quality dictates the regulatory effects of MET on mTOR and OXPHOS. Once overloaded, mitochondrial reactive oxygen species (ROS) inhibits mTOR activity and OXPHOS performance to prevent mitochondrial dysfunction-induced tumor cell death, by disrupting MET dimerization to block its autophosphorylation and interaction with vacuol

SUBMITTER: Huang X 

PROVIDER: S-EPMC7708774 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature