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

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...

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Autores principales: Chun, Sang Y, Johnson, Craig, Washburn, Joseph G, Cruz-Correa, Marcia R, Dang, Duyen T, Dang, Long H
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2999617/
https://www.ncbi.nlm.nih.gov/pubmed/21073737
http://dx.doi.org/10.1186/1476-4598-9-293
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author Chun, Sang Y
Johnson, Craig
Washburn, Joseph G
Cruz-Correa, Marcia R
Dang, Duyen T
Dang, Long H
author_facet Chun, Sang Y
Johnson, Craig
Washburn, Joseph G
Cruz-Correa, Marcia R
Dang, Duyen T
Dang, Long H
author_sort Chun, Sang Y
collection PubMed
description 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 HCT116(WT KRAS), HCT116(HIF-1α-/-), HCT116(HIF-2α-/-), and HCT116(HIF-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. CONCLUSION: Our findings suggest novel strategies for treating tumors with oncogenic KRAS mutations.
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spelling pubmed-29996172010-12-09 Oncogenic KRAS modulates mitochondrial metabolism in human colon cancer cells by inducing HIF-1α and HIF-2α target genes Chun, Sang Y Johnson, Craig Washburn, Joseph G Cruz-Correa, Marcia R Dang, Duyen T Dang, Long H Mol Cancer Research 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 HCT116(WT KRAS), HCT116(HIF-1α-/-), HCT116(HIF-2α-/-), and HCT116(HIF-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. CONCLUSION: Our findings suggest novel strategies for treating tumors with oncogenic KRAS mutations. BioMed Central 2010-11-13 /pmc/articles/PMC2999617/ /pubmed/21073737 http://dx.doi.org/10.1186/1476-4598-9-293 Text en Copyright ©2010 Chun et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Chun, Sang Y
Johnson, Craig
Washburn, Joseph G
Cruz-Correa, Marcia R
Dang, Duyen T
Dang, Long H
Oncogenic KRAS modulates mitochondrial metabolism in human colon cancer cells by inducing HIF-1α and HIF-2α target genes
title Oncogenic KRAS modulates mitochondrial metabolism in human colon cancer cells by inducing HIF-1α and HIF-2α target genes
title_full Oncogenic KRAS modulates mitochondrial metabolism in human colon cancer cells by inducing HIF-1α and HIF-2α target genes
title_fullStr Oncogenic KRAS modulates mitochondrial metabolism in human colon cancer cells by inducing HIF-1α and HIF-2α target genes
title_full_unstemmed Oncogenic KRAS modulates mitochondrial metabolism in human colon cancer cells by inducing HIF-1α and HIF-2α target genes
title_short Oncogenic KRAS modulates mitochondrial metabolism in human colon cancer cells by inducing HIF-1α and HIF-2α target genes
title_sort oncogenic kras modulates mitochondrial metabolism in human colon cancer cells by inducing hif-1α and hif-2α target genes
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2999617/
https://www.ncbi.nlm.nih.gov/pubmed/21073737
http://dx.doi.org/10.1186/1476-4598-9-293
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