Open AccessCombinational therapy targeting the MET‐mTOR‐ROS loop disrupts mitochondrial autoregulatory machinery of liver cancer
Author(s) -
Huang Xing,
Zhang Gang,
Bai Xueli,
Liang Tingbo
Publication year - 2020
Publication title -
clinical and translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.125
H-Index - 1
ISSN - 2001-1326
DOI - 10.1002/ctm2.237
Subject(s) - pi3k/akt/mtor pathway , cancer research , autophosphorylation , oxidative phosphorylation , mitochondrion , microbiology and biotechnology , mtorc2 , mechanistic target of rapamycin , phosphorylation , biology , chemistry , signal transduction , mtorc1 , biochemistry , protein kinase a
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 vacuolar ATP synthase (V‐ATPase). The MET‐mTOR‐ROS loop acts as a protective checkpoint in liver cancer, and thus this autoregulatory machinery is a promising combinational target for liver cancer therapy.