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

• Published in: Molecular cancer Vol. 9; p. 293
• Main Authors: Chun, Sang Y, Johnson, Craig, Washburn, Joseph G, Cruz-Correa, Marcia R, Dang, Duyen T, Dang, Long H
• Format: Journal Article
• Language: English
• Published: London BioMed Central Ltd 13.11.2010; BioMed Central
• Subjects: Angiogenesis; Biomedical research; Care and treatment; Cellular signal transduction; Cloning; Colleges & universities; Colon cancer; Enzymes; Flow cytometry; Gene expression; Gene loci; Gene mutations; Genetic aspects; Glucose; Health aspects; Hypoxia; Internal medicine; Kinases; Oncogenes; Physiological aspects; United States
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/1476-4598-9-293

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.sup.WT KRAS.sup., HCT116.sup.HIF-1[alpha]-/-.sup., HCT116.sup.HIF-2[alpha]-/-.sup., and HCT116.sup.HIF-1[alpha]-/-HIF-2[alpha]-/- .sup.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.