Dataset Information
Oncogenic KRAS modulates mitochondrial metabolism in human colon cancer cells by inducing HIF-1? and HIF-2? target genes.
Ontology highlight
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-1? and -2? (HIF-1? and HIF-2?) are activated in cancer due to dysregulated ras signaling.Methods
To understand the individual and combined roles of HIF-1? and HIF-2? in cancer metabolism and oncogenic KRAS signaling, we used targeted homologous recombination to disrupt the oncogenic KRAS, HIF-1?, and HIF-2? gene loci in HCT116 colon cancer cells to generate isogenic HCT116WT KRAS, HCT116HIF-1?-/-, HCT116HIF-2?-/-, and HCT116HIF-1?-/-HIF-2?-/- cell lines.Results
Global gene expression analyses of these cell lines reveal that HIF-1? and HIF-2? work together to modulate cancer metabolism and regulate genes signature overlapping with oncogenic KRAS. Cancer cells with disruption of both HIF-1? and HIF-2? 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.
SUBMITTER: Chun SY
PROVIDER: S-EPMC2999617 | biostudies-literature | 2010 Nov
REPOSITORIES: biostudies-literature
Publications
Oncogenic KRAS modulates mitochondrial metabolism in human colon cancer cells by inducing HIF-1α and HIF-2α target genes.
Molecular cancer 20101113
<h4>Background</h4>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.<h4>Methods</h4>To understand the individual and combined ...[more]