MET Inhibition Elicits PGC1α-Dependent Metabolic Reprogramming in Glioblastoma.

ABSTRACT: The receptor kinase c-MET has emerged as a target for glioblastoma therapy. However, treatment resistance emerges inevitably. Here, we performed global metabolite screening with metabolite set enrichment coupled with transcriptome and gene set enrichment analysis and proteomic screening, and identified substantial reprogramming of tumor metabolism involving oxidative phosphorylation and fatty acid oxidation (FAO) with substantial accumulation of acyl-carnitines accompanied by an increase of PGC1α in response to genetic (shRNA and CRISPR/Cas9) and pharmacologic (crizotinib) inhibition of c-MET. Extracellular flux and carbon tracing analyses (U-¹³C-glucose, U-¹³C-glutamine, and U-¹³C-palmitic acid) demonstrated enhanced oxidative metabolism, which was driven

SUBMITTER: Zhang Y 

PROVIDER: S-EPMC6942623 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature