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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: BACKGROUND, METHODS, RESULTS. Meshes: Adenosine Triphosphate, Basic Helix-Loop-Helix Transcription Factors, Blotting, Western, Cell Line, Tumor, Colonic Neoplasms, Gene Expression Profiling, HCT116 Cells, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Mitochondria, Mutagenesis, Site-Directed, Oxygen Consumption, Proto-Oncogene Proteins, Proto-Oncogene Proteins p21(ras), Reactive Oxygen Species, Reverse Transcriptase Polymerase Chain Reaction, ras Proteins.
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Does oncogenic KRAS modulate mitochondrial metabolism in human colon cancer cells by inducing HIF-1α and HIF-2α target genes? Context: 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-1α and -2α (HIF-1α and HIF-2α) are activated in cancer due to dysregulated ras signaling. 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 KRAS, HIF-1α, and HIF-2α gene loci in HCT116 colon cancer cells to generate isogenic HCT116WT KRAS, HCT116HIF-1α-/-, HCT116HIF-2α-/-, and HCT116HIF-1α-/-HIF-2α-/- cell lines. 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 HIF-1α and HIF-2α or oncogenic KRAS showed decreased aerobic respiration and ATP production, with increased ROS generation.
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Our findings suggest novel strategies for treating tumors with oncogenic KRAS mutations. Final Decision: yes