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

Autophagy
Xing HuangWei Xie

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-...Continue Reading

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Citations

Jun 27, 2020·Frontiers in Cell and Developmental Biology·Valentina SoraElena Papaleo
Aug 9, 2020·Signal Transduction and Targeted Therapy·Xing HuangTingbo Liang
Aug 9, 2020·Cancer Management and Research·Huining TianGuixia Wang
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Mar 3, 2020·Frontiers in Cell and Developmental Biology·Haiyu WangZujiang Yu
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May 22, 2020·Frontiers in Cell and Developmental Biology·Xing HuangTingbo Liang
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Methods Mentioned

BETA
co-immunoprecipitation
immunoprecipitation assay
immunoprecipitation
fluorescence microscopy
chips
xenograft
xenografts
transfection
FACS
PCR

Software Mentioned

R
Cytoscape
MetaboAnalyst
GraphPad Prism
Excel
Compound Discoverer
pheatmap
SIMCA
ImageQuant
XCMS

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