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

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.

USP22 Deubiquitinates CD274 to Suppress Anticancer Immunity

“…According to previously established protocols (15), after two washes with ice-cold PBS, 5 Â 10 5 cells were resuspended in lysis buffer (25 mmol/L HEPES pH 7.5, 150 mmol/L NaCl, 0.25% Triton X-100, 0.25% NP-40, 0.25% CHAPS, 10% glycerol, and 1 Â protease inhibitor cocktail) on ice for 1.5 hours, and then centrifuged at 13,000 g for 15 minutes. The supernatants were precleared with 40 mL protein A/G-coupled agarose (sc-2003, Santa Cruz) for 1.5 hours and then incubated with 2 mg of the indicated antibodies, isotype control IgG (co-IgG)-conjugated beads, or 20 mL anti-Flag affinity gel (B23101, Bimake) for another 4 hours at 4 C. After three washes with lysis buffer, immunoprecipitates were boiled in 1 Â loading buffer for Western blot analysis.…”

Metformin reduces HGF-induced resistance to alectinib via the inhibition of Gab1

“…Researchers have previously showed that HGF reduces susceptibility to alectinib by mainly restoring the downstream AKT and ERK pathways via MET activation, and the AKT-mTOR axis has important roles in the HGF/ MET pathway 12,34 . This research found that metformin selectively inhibited the abnormal phosphorylation of AKT, mTOR, ERK, P70S6K, and S6 in the presence of HGF but had no effect on the phosphorylation of MET, regardless of the absence or presence of alectinib.…”

Prognostic significance ofSOCS1andSOCS3tumor suppressors in hepatocellular carcinoma and its correlation to key oncogenic signaling pathways

“…However, none of these four genes were able to independently predict patient survival within the TCGA-LIHC dataset ( Figure 3C). This notion is supported by the failure of MET-targeting therapeutics to improve survival outcome that has been recently attributed, at least partly, to the ability of kinase-inhibited MET to promote cell survival via promoting autophagy [75]. Even though MET expression alone was not predictive, ERBB3, which contributes to the resistance to MET inhibition [76] displayed a high predictive potential ( Supplementary Table 1).…”