The HGF-MET axis coordinates liver cancer metabolism and autophagy for chemotherapeutic resistance

Autophagy. 2019 Jul;15(7):1258-1279. doi: 10.1080/15548627.2019.1580105. Epub 2019 Feb 20.

Abstract

Notwithstanding the numerous drugs available for liver cancer, emerging evidence suggests that chemotherapeutic resistance is a significant issue. HGF and its receptor MET play critical roles in liver carcinogenesis and metastasis, mainly dependent on the activity of receptor tyrosine kinase. However, for unknown reasons, all HGF-MET kinase activity-targeted drugs have failed or have been suspended in clinical trials thus far. Macroautophagy/autophagy is a protective 'self-eating' process for resisting metabolic stress by recycling obsolete components, whereas the impact of autophagy-mediated reprogrammed metabolism on therapeutic resistance is largely unclear, especially in liver cancer. In the present study, we first observed that HGF stimulus facilitated the Warburg effect and glutaminolysis to promote biogenesis in multiple liver cancer cells. We then identified the pyruvate dehydrogenase complex (PDHC) and GLS/GLS1 as crucial substrates of HGF-activated MET kinase; MET-mediated phosphorylation inhibits PDHC activity but activates GLS to promote cancer cell metabolism and biogenesis. We further found that the key residues of kinase activity in MET (Y1234/1235) also constitute a conserved LC3-interacting region motif (Y1234-Y1235-x-V1237). Therefore, on inhibiting HGF-mediated MET kinase activation, Y1234/1235-dephosphorylated MET induced autophagy to maintain biogenesis for cancer cell survival. Moreover, we verified that Y1234/1235-dephosphorylated MET correlated with autophagy in clinical liver cancer. Finally, a combination of MET inhibitor and autophagy suppressor significantly improved the therapeutic efficiency of liver cancer in vitro and in mice. Together, our findings reveal an HGF-MET axis-coordinated functional interaction between tyrosine kinase signaling and autophagy, and establish a MET-autophagy double-targeted strategy to overcome chemotherapeutic resistance in liver cancer. Abbreviations: ALDO: aldolase, fructose-bisphosphate; CQ: chloroquine; DLAT/PDCE2: dihydrolipoamide S-acetyltransferase; EMT: epithelial-mesenchymal transition; ENO: enolase; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GLS/GLS1: glutaminase; GLUL/GS: glutamine-ammonia ligase; GPI/PGI: glucose-6-phosphate isomerase; HCC: hepatocellular carcinoma; HGF: hepatocyte growth factor; HK: hexokinase; LDH: lactate dehydrogenase; LIHC: liver hepatocellular carcinoma; LIR: LC3-interacting region; PDH: pyruvate dehydrogenase; PDHA1: pyruvate dehydrogenase E1 alpha 1 subunit; PDHX: pyruvate dehydrogenase complex component X; PFK: phosphofructokinase; PK: pyruvate kinase; RTK: receptor tyrosine kinase; TCGA: The Cancer Genome Atlas.

Keywords: Biogenesis; Warburg effect; combined treatment; glutaminolysis; targeted therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / drug effects*
  • Autophagy / genetics*
  • Carcinoma, Hepatocellular / drug therapy
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Drug Resistance, Neoplasm / drug effects
  • Drug Therapy, Combination
  • Glutaminase / chemistry
  • Glutaminase / genetics
  • Glutaminase / metabolism
  • Hep G2 Cells
  • Hepatocyte Growth Factor / genetics
  • Hepatocyte Growth Factor / metabolism*
  • Humans
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Male
  • Mice
  • Mice, Nude
  • Phosphorylation
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism*
  • Pyruvate Dehydrogenase Complex / antagonists & inhibitors*
  • Pyruvate Dehydrogenase Complex / chemistry
  • Pyruvate Dehydrogenase Complex / genetics
  • Pyruvate Dehydrogenase Complex / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Transplantation, Heterologous

Substances

  • HGF protein, human
  • Pyruvate Dehydrogenase Complex
  • Hepatocyte Growth Factor
  • MET protein, human
  • Proto-Oncogene Proteins c-met
  • TOR Serine-Threonine Kinases
  • Glutaminase

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (81502975 to X.H.), China Postdoctoral Science Foundation (2016T90413 and 2015M581693 to X.H.), and SEU-Alphamab Joint Center (SA2015001 to W.X.). The research was funded in part by Jiangsu Planned Projects for Postdoctoral Research Funds (1501002A to X.H.) and Fundamental Research Funds for the Central Universities (2242016R20027 and 2242016K41045 to X.H.).