title: Oncogenic KRAS modulates mitochondrial metabolism in human colon cancer cells by inducing HIF-1α and HIF-2α target genes.
abstract: 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-1α and -2α (HIF-1α and HIF-2α) are activated in cancer due to dysregulated ras signaling.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Our findings suggest novel strategies for treating tumors with oncogenic KRAS mutations.
authors.affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
authors.forename: Sang Y
authors.initials: SY
authors.lastname: Chun
authors.forename: Craig
authors.initials: C
authors.lastname: Johnson
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Washburn
authors.forename: Marcia R
authors.initials: MR
authors.lastname: Cruz-Correa
authors.forename: Duyen T
authors.initials: DT
authors.lastname: Dang
authors.forename: Long H
authors.initials: LH
authors.lastname: Dang
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D045325:HCT116 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D010101:Oxygen Consumption / Q000235:genetics / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000255:Adenosine Triphosphate; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D017382:Reactive Oxygen Species; D018631:ras Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C117307:KRAS protein, human