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

• Main Authors: Dang Duyen T, Cruz-Correa Marcia R, Washburn Joseph G, Johnson Craig, Chun Sang Y, Dang Long H
• Format: Article
• Language: English
• Published: BMC 2010-11-01
• Series: Molecular Cancer
• Online Access: http://www.molecular-cancer.com/content/9/1/293
• ISSN: 1476-4598

<p>Abstract</p> <p>Background</p> <p>Activating <it>KRAS </it>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-1α and -2α (HIF-1α and HIF-2α) are activated in cancer due to dysregulated ras signaling.</p> <p>Methods</p> <p>To understand the individual and combined roles of HIF-1α and HIF-2α in cancer metabolism and oncogenic KRAS signaling, we used targeted homologous recombination to disrupt the oncogenic <it>KRAS</it>, <it>HIF-1α</it>, and <it>HIF-2α </it>gene loci in HCT116 colon cancer cells to generate isogenic HCT116^{WT KRAS}, HCT116^HIF-1α-/-, HCT116^HIF-2α-/-, and HCT116^{HIF-1α-/-HIF-2α-/-}cell lines.</p> <p>Results</p> <p>Global gene expression analyses of these cell lines reveal that HIF-1α and HIF-2α work together to modulate cancer metabolism and regulate genes signature overlapping with oncogenic KRAS. Cancer cells with disruption of both <it>HIF-1α </it>and <it>HIF-2α </it>or oncogenic <it>KRAS </it>showed decreased aerobic respiration and ATP production, with increased ROS generation.</p> <p>Conclusion</p> <p>Our findings suggest novel strategies for treating tumors with oncogenic <it>KRAS </it>mutations.</p>