The HGF-MET axis coordinates liver cancer metabolism and autophagy for chemotherapeutic resistance.
Autophagy
; 15(7): 1258-1279, 2019 07.
Article
en En
| MEDLINE
| ID: mdl-30786811
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Complejo Piruvato Deshidrogenasa
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Autofagia
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Transducción de Señal
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Factor de Crecimiento de Hepatocito
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Proteínas Proto-Oncogénicas c-met
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Neoplasias Hepáticas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Autophagy
Año:
2019
Tipo del documento:
Article
País de afiliación:
China