13C Isotopic Tracers to Elucidate Metabolic Dependences of Renal Cell Carcinoma Cells

Currently evolving paradigms in cancer biology support the view that transcription factors and gene deregulation impinge on the metabolism of cancer cells to support biosynthesis and accelerated growth. This recognition calls for the use of stable isotopic tracers to identify metabolic switches that are associated with malignancy. Hypoxia is a hallmark of the tumor microenvironment and we previously showed using ¹³C isotopic tracers that hypoxic cells, while diverting most of the glucose to lactate production, use glutamine to generate lipids through reductive carboxylation of alpha-ketoglutarate, or reductive TCA cycle. We will show that the reductive TCA cycle is a metabolic signature of hypoxia inducible factors (HIF) expression in renal cell carcinoma (RCC) cells and that targeting this pathway may provide a novel therapeutic strategy for the treatment of tumors deficient in the VHL tumor suppressor protein. This work highlights how ¹³C isotopic tracers can elucidate the metabolic transformation of cancer cells.