Oncogenic KRAS modulates mitochondrial metabolism in human colon cancer cells by inducing HIF-1α and HIF-2α target genes

Background: Activating KRAS mutations are important for cancer initiation and progression; and have recently been shown to cause primary resistance to therapies targeting the epidermal growth factor receptor. Therefore, strategies are currently in development to overcome treatment resistance due to oncogenic KRAS. The hypoxia-inducible factors-1 alpha and -2 alpha (HIF-1 alpha and HIF-2 alpha) are activated in cancer due to dysregulated ras signaling. Methods: To understand the individual and combined roles of HIF-1 alpha and HIF-2 alpha in cancer metabolism and oncogenic KRAS signaling, we used targeted homologous recombination to disrupt the oncogenic KRAS, HIF-1 alpha, and HIF-2 alpha gene loci in HCT116 colon cancer cells to generate isogenic HCT116(WT) (KRAS), HCT116(HIF-1 alpha-/-), HCT116(HIF-2a-/-), and HCT116(HIF-1 alpha-/-HIF-2 alpha-/-) cell lines. Results: Global gene expression analyses of these cell lines reveal that HIF-1 alpha and HIF-2 alpha work together to modulate cancer metabolism and regulate genes signature overlapping with oncogenic KRAS. Cancer cells with disruption of both HIF-1 alpha and HIF-2 alpha or oncogenic KRAS showed decreased aerobic respiration and ATP production, with increased ROS generation. Conclusion: Our findings suggest novel strategies for treating tumors with oncogenic KRAS mutations.