Targeting one-carbon metabolism in cancer

Folate metabolism supplies one-carbon (1C) units for nucleotide biosynthesis and has long been a target for cancer chemotherapy. Mitochondrial serine catabolism is considered the sole contributor of folate-mediated 1C units in tumors; and serine-derived 1C flux was reported to far exceed the anabolic requirements of cancer cells – a phenomenon referred to as ‘overflow metabolism’. Here, we show that the concentration of folate in the cell environment determines the relative contribution of the cytosolic and mitochondrial folate pathway. Surprisingly, under physiological folate levels, cytosolic serine-hydroxymethyltransferase (SHMT1) is the predominant source for 1C units in a variety of cancers, while mitochondrial 1C flux is overly repressed. We show that tumor-specific reliance on SHMT1 is associated with poor capacity to retain intracellular folates, which is determined by the expression of the reduced folate carrier (RFC). Studying glycine-derived 1C flux, we found substantially high expression of glycine-cleavage system (GCS) genes in hepatocellular carcinoma (HCC). We developed a novel experimental-computational approach for quantifying GCS flux, confirming induced glycine cleavage flux in HCC, providing 1C units for nucleotide biosynthesis. Inhibition of GCS by silencing of glycine-decarboxylase (GLDC) significantly inhibits tumor growth in mouse xenograft models; suggesting GCS as a novel target for HCC - the most common and highly malignant type of primary liver cancer. Overall, our findings reveal major diversity in tumor-specific 1C metabolic fluxes and molecular markers for induced dependence on specific serine and glycine catabolic enzymes.