The insulin-like growth factor 2 mRNA-binding protein 2 affects tumor cell metabolism via mitochondrial transporter activity and lipid alterations.

Abstract

The insulin-like growth factor 2 mRNA-binding protein (IGF2BP) family is overexpressed in cancer and associated with poor prognosis. IGF2BP2 has been linked to single metabolic alterations by acting on its RNA targets. Here, we used a comprehensive approach to elucidate the effects of IGF2BP2 on primary and lipid metabolism. 13C-metabolic flux analysis (MFA) combined with RNA-Seq data revealed that IGF2BP2 affects mitochondrial fluxes by regulating the expression of several mitochondrial transporters, such as mitochondrial pyruvate carrier 1 (MPC1) and uncoupling protein 2 (UCP2). Methyl pyruvate reversed the gene expression patterns of UCP2 and CPT1A in HCT116 IGF2BP2 knockout (KO) cells by bypassing MPC1. Interestingly, an altered expression of the transporter UCP2 was also observed in a patient-derived tumor organoid (PDO), in which IGF2BP2 was knocked down. The altered glutamine metabolism seen in the 13C-MFA and the citrate label data derived from extracted mitochondria confirm a rerouting of glutamine almost exclusively into the mitochondria and a reduction of glycolytic carbon intake into the mitochondria. Due to changes in palmitate labeling patterns, lipid stainings were performed, suggesting lipid accumulation in KO cells. A lipidomic analysis revealed altered compositions across almost all lipid species. Further, lipogenic genes involved in fatty acid and cholesterol metabolism were differentially expressed. Most of the differentially expressed genes are potential direct targets of IGF2BP2 based on publicly available IGF2BP2 CLIP data. Overall, these results show the influence of IGF2BP2 on the central carbon metabolism of cancer cells, primarily through its effects on MPC1 and the resulting effects on UCP2. The complex interaction of IGF2BP2 with the metabolic network provides important insights into tumor metabolism, particularly relevant to tumor growth and resistance to therapy.