ERRα-Regulated Lactate Metabolism Contributes to Resistance to Targeted Therapies in Breast Cancer
Imaging studies in animals and in humans have indicated that the oxygenation and nutritional status of solid tumors is dynamic. Furthermore, the extremely low level of glucose within tumors, while reflecting its rapid uptake and metabolism, also suggests that cancer cells must rely on other energy s...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2016-04-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124716302820 |
| _version_ | 1818547972622778368 |
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| author | Sunghee Park Ching-Yi Chang Rachid Safi Xiaojing Liu Robert Baldi Jeff S. Jasper Grace R. Anderson Tingyu Liu Jeffrey C. Rathmell Mark W. Dewhirst Kris C. Wood Jason W. Locasale Donald P. McDonnell |
| author_facet | Sunghee Park Ching-Yi Chang Rachid Safi Xiaojing Liu Robert Baldi Jeff S. Jasper Grace R. Anderson Tingyu Liu Jeffrey C. Rathmell Mark W. Dewhirst Kris C. Wood Jason W. Locasale Donald P. McDonnell |
| author_sort | Sunghee Park |
| collection | DOAJ |
| description | Imaging studies in animals and in humans have indicated that the oxygenation and nutritional status of solid tumors is dynamic. Furthermore, the extremely low level of glucose within tumors, while reflecting its rapid uptake and metabolism, also suggests that cancer cells must rely on other energy sources in some circumstances. Here, we find that some breast cancer cells can switch to utilizing lactate as a primary source of energy, allowing them to survive glucose deprivation for extended periods, and that this activity confers resistance to PI3K/mTOR inhibitors. The nuclear receptor, estrogen-related receptor alpha (ERRα), was shown to regulate the expression of genes required for lactate utilization, and isotopomer analysis revealed that genetic or pharmacological inhibition of ERRα activity compromised lactate oxidation. Importantly, ERRα antagonists increased the in vitro and in vivo efficacy of PI3K/mTOR inhibitors, highlighting the potential clinical utility of this drug combination. |
| first_indexed | 2024-12-12T08:13:46Z |
| format | Article |
| id | doaj.art-8b3b7d737fc9404299f8033052271ea4 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-12T08:13:46Z |
| publishDate | 2016-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-8b3b7d737fc9404299f8033052271ea42022-12-22T00:31:41ZengElsevierCell Reports2211-12472016-04-0115232333510.1016/j.celrep.2016.03.026ERRα-Regulated Lactate Metabolism Contributes to Resistance to Targeted Therapies in Breast CancerSunghee Park0Ching-Yi Chang1Rachid Safi2Xiaojing Liu3Robert Baldi4Jeff S. Jasper5Grace R. Anderson6Tingyu Liu7Jeffrey C. Rathmell8Mark W. Dewhirst9Kris C. Wood10Jason W. Locasale11Donald P. McDonnell12Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USADepartment of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USADepartment of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USADepartment of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USADepartment of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USADepartment of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USADepartment of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USADepartment of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USADepartment of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USADepartment of Radiation Oncology, Duke University School of Medicine, Durham, NC 27710, USADepartment of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USADepartment of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USADepartment of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USAImaging studies in animals and in humans have indicated that the oxygenation and nutritional status of solid tumors is dynamic. Furthermore, the extremely low level of glucose within tumors, while reflecting its rapid uptake and metabolism, also suggests that cancer cells must rely on other energy sources in some circumstances. Here, we find that some breast cancer cells can switch to utilizing lactate as a primary source of energy, allowing them to survive glucose deprivation for extended periods, and that this activity confers resistance to PI3K/mTOR inhibitors. The nuclear receptor, estrogen-related receptor alpha (ERRα), was shown to regulate the expression of genes required for lactate utilization, and isotopomer analysis revealed that genetic or pharmacological inhibition of ERRα activity compromised lactate oxidation. Importantly, ERRα antagonists increased the in vitro and in vivo efficacy of PI3K/mTOR inhibitors, highlighting the potential clinical utility of this drug combination.http://www.sciencedirect.com/science/article/pii/S2211124716302820 |
| spellingShingle | Sunghee Park Ching-Yi Chang Rachid Safi Xiaojing Liu Robert Baldi Jeff S. Jasper Grace R. Anderson Tingyu Liu Jeffrey C. Rathmell Mark W. Dewhirst Kris C. Wood Jason W. Locasale Donald P. McDonnell ERRα-Regulated Lactate Metabolism Contributes to Resistance to Targeted Therapies in Breast Cancer Cell Reports |
| title | ERRα-Regulated Lactate Metabolism Contributes to Resistance to Targeted Therapies in Breast Cancer |
| title_full | ERRα-Regulated Lactate Metabolism Contributes to Resistance to Targeted Therapies in Breast Cancer |
| title_fullStr | ERRα-Regulated Lactate Metabolism Contributes to Resistance to Targeted Therapies in Breast Cancer |
| title_full_unstemmed | ERRα-Regulated Lactate Metabolism Contributes to Resistance to Targeted Therapies in Breast Cancer |
| title_short | ERRα-Regulated Lactate Metabolism Contributes to Resistance to Targeted Therapies in Breast Cancer |
| title_sort | errα regulated lactate metabolism contributes to resistance to targeted therapies in breast cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124716302820 |
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