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HIF-1-alpha links mitochondrial perturbation to the dynamic acquisition of breast cancer tumorigenicity
Up-regulation of hypoxia-inducible factor-1α (HIF-1α), even in normoxia, is a common feature of solid malignancies. However, the mechanisms of increased HIF-1α abundance, and its role in regulating breast cancer plasticity are not fully understood. We have previously demonstrated that dimethyl-2-ket...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085137/ https://www.ncbi.nlm.nih.gov/pubmed/27058900 http://dx.doi.org/10.18632/oncotarget.8570 |
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author | Kuo, Ching-Ying Cheng, Chun-Ting Hou, Peifeng Lin, Yi-Pei Ma, Huimin Chung, Yiyin Chi, Kevin Chen, Yuan Li, Wei Kung, Hsing-Jien Ann, David K. |
author_facet | Kuo, Ching-Ying Cheng, Chun-Ting Hou, Peifeng Lin, Yi-Pei Ma, Huimin Chung, Yiyin Chi, Kevin Chen, Yuan Li, Wei Kung, Hsing-Jien Ann, David K. |
author_sort | Kuo, Ching-Ying |
collection | PubMed |
description | Up-regulation of hypoxia-inducible factor-1α (HIF-1α), even in normoxia, is a common feature of solid malignancies. However, the mechanisms of increased HIF-1α abundance, and its role in regulating breast cancer plasticity are not fully understood. We have previously demonstrated that dimethyl-2-ketoglutarate (DKG), a widely used cell membrane-permeable α-ketoglutarate (α-KG) analogue, transiently stabilizes HIF-1α by inhibiting prolyl hydroxylase 2. Here, we report that breast cancer tumorigenicity can be acquired through prolonged treatment with DKG. Our results indicate that, in response to prolonged DKG treatment, mitochondrial respiration becomes uncoupled, leading to the accumulation of succinate and fumarate in breast cancer cells. Further, we found that an early increase in the oxygen flux rate was accompanied by a delayed enhancement of glycolysis. Together, our results indicate that these events trigger a dynamic enrichment for cells with pluripotent/stem-like cell markers and tumorsphere-forming capacity. Moreover, DKG-mediated metabolic reprogramming results in HIF-1α induction and reductive carboxylation pathway activation. Both HIF-1α accumulation and the tumor-promoting metabolic state are required for DKG-promoted tumor repopulation capacity in vivo. Our data suggest that mitochondrial adaptation to DKG elevates the ratio of succinate or fumarate to α-KG, which in turn stabilizes HIF-1α and reprograms breast cancer cells into a stem-like state. Therefore, our results demonstrate that metabolic regulation, with succinate and/or fumarate accumulation, governs the dynamic transition of breast cancer tumorigenic states and we suggest that HIF-1α is indispensable for breast cancer tumorigenicity. |
format | Online Article Text |
id | pubmed-5085137 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-50851372016-10-31 HIF-1-alpha links mitochondrial perturbation to the dynamic acquisition of breast cancer tumorigenicity Kuo, Ching-Ying Cheng, Chun-Ting Hou, Peifeng Lin, Yi-Pei Ma, Huimin Chung, Yiyin Chi, Kevin Chen, Yuan Li, Wei Kung, Hsing-Jien Ann, David K. Oncotarget Research Paper Up-regulation of hypoxia-inducible factor-1α (HIF-1α), even in normoxia, is a common feature of solid malignancies. However, the mechanisms of increased HIF-1α abundance, and its role in regulating breast cancer plasticity are not fully understood. We have previously demonstrated that dimethyl-2-ketoglutarate (DKG), a widely used cell membrane-permeable α-ketoglutarate (α-KG) analogue, transiently stabilizes HIF-1α by inhibiting prolyl hydroxylase 2. Here, we report that breast cancer tumorigenicity can be acquired through prolonged treatment with DKG. Our results indicate that, in response to prolonged DKG treatment, mitochondrial respiration becomes uncoupled, leading to the accumulation of succinate and fumarate in breast cancer cells. Further, we found that an early increase in the oxygen flux rate was accompanied by a delayed enhancement of glycolysis. Together, our results indicate that these events trigger a dynamic enrichment for cells with pluripotent/stem-like cell markers and tumorsphere-forming capacity. Moreover, DKG-mediated metabolic reprogramming results in HIF-1α induction and reductive carboxylation pathway activation. Both HIF-1α accumulation and the tumor-promoting metabolic state are required for DKG-promoted tumor repopulation capacity in vivo. Our data suggest that mitochondrial adaptation to DKG elevates the ratio of succinate or fumarate to α-KG, which in turn stabilizes HIF-1α and reprograms breast cancer cells into a stem-like state. Therefore, our results demonstrate that metabolic regulation, with succinate and/or fumarate accumulation, governs the dynamic transition of breast cancer tumorigenic states and we suggest that HIF-1α is indispensable for breast cancer tumorigenicity. Impact Journals LLC 2016-04-04 /pmc/articles/PMC5085137/ /pubmed/27058900 http://dx.doi.org/10.18632/oncotarget.8570 Text en Copyright: © 2016 Kuo et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Kuo, Ching-Ying Cheng, Chun-Ting Hou, Peifeng Lin, Yi-Pei Ma, Huimin Chung, Yiyin Chi, Kevin Chen, Yuan Li, Wei Kung, Hsing-Jien Ann, David K. HIF-1-alpha links mitochondrial perturbation to the dynamic acquisition of breast cancer tumorigenicity |
title | HIF-1-alpha links mitochondrial perturbation to the dynamic acquisition of breast cancer tumorigenicity |
title_full | HIF-1-alpha links mitochondrial perturbation to the dynamic acquisition of breast cancer tumorigenicity |
title_fullStr | HIF-1-alpha links mitochondrial perturbation to the dynamic acquisition of breast cancer tumorigenicity |
title_full_unstemmed | HIF-1-alpha links mitochondrial perturbation to the dynamic acquisition of breast cancer tumorigenicity |
title_short | HIF-1-alpha links mitochondrial perturbation to the dynamic acquisition of breast cancer tumorigenicity |
title_sort | hif-1-alpha links mitochondrial perturbation to the dynamic acquisition of breast cancer tumorigenicity |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085137/ https://www.ncbi.nlm.nih.gov/pubmed/27058900 http://dx.doi.org/10.18632/oncotarget.8570 |
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