دورية أكاديمية
AMPK-deficiency forces metformin-challenged cancer cells to switch from carbohydrate metabolism to ketogenesis to support energy metabolism.
| العنوان: | AMPK-deficiency forces metformin-challenged cancer cells to switch from carbohydrate metabolism to ketogenesis to support energy metabolism. |
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| المؤلفون: | Palma FR; Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.; Department of Medicine and Biophysics, Medical College of Wisconsin, Milwaukee, WI, 5322, USA., Ratti BA; Universidade Estadual de Maringa, Avenida Colombo 5790, Maringa, PR, CEP 87020-900, Brazil., Paviani V; Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.; Department of Medicine and Biophysics, Medical College of Wisconsin, Milwaukee, WI, 5322, USA., Coelho DR; Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.; Department of Medicine and Biophysics, Medical College of Wisconsin, Milwaukee, WI, 5322, USA., Miguel R; Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA., Danes JM; Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.; Department of Medicine and Biophysics, Medical College of Wisconsin, Milwaukee, WI, 5322, USA., Zaichik SV; Department of Medicine, University of Illinois at Chicago, 909 S. Wolcott Avenue, COMRB 1131, Chicago, IL, 60612, USA., de Abreu AL; Universidade Estadual de Maringa, Avenida Colombo 5790, Maringa, PR, CEP 87020-900, Brazil.; Department of Medicine, University of Illinois at Chicago, 909 S. Wolcott Avenue, COMRB 1131, Chicago, IL, 60612, USA., Silva SO; Universidade Estadual de Maringa, Avenida Colombo 5790, Maringa, PR, CEP 87020-900, Brazil., Chen Y; Department of Medicine and Biophysics, Medical College of Wisconsin, Milwaukee, WI, 5322, USA.; Blood Research Institute, Versiti, Milwaukee, WI, 53226, USA., Silverstein RL; Department of Medicine and Biophysics, Medical College of Wisconsin, Milwaukee, WI, 5322, USA.; Blood Research Institute, Versiti, Milwaukee, WI, 53226, USA., Karan U; Department of Medicine, Emory University School of Medicine, 615 Michael Street NE, Atlanta, GA, 30322, USA., Jones DP; Department of Medicine, Emory University School of Medicine, 615 Michael Street NE, Atlanta, GA, 30322, USA., Bonini MG; Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. marcelo.bonini@northwestern.edu.; Department of Medicine and Biophysics, Medical College of Wisconsin, Milwaukee, WI, 5322, USA. marcelo.bonini@northwestern.edu. |
| المصدر: | Oncogene [Oncogene] 2021 Sep; Vol. 40 (36), pp. 5455-5467. Date of Electronic Publication: 2021 Jul 21. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8711562 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5594 (Electronic) Linking ISSN: 09509232 NLM ISO Abbreviation: Oncogene Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: <2002->: Basingstoke : Nature Publishing Group Original Publication: Basingstoke, Hampshire, UK : Scientific & Medical Division, MacMillan Press, c1987- |
| مواضيع طبية MeSH: | AMP-Activated Protein Kinases* , Metformin*, Breast Neoplasms ; Carbohydrate Metabolism ; Energy Metabolism ; Glycolysis ; Humans |
| مستخلص: | Epidemiologic studies in diabetic patients as well as research in model organisms have indicated the potential of metformin as a drug candidate for the treatment of various types of cancer, including breast cancer. To date most of the anti-cancer properties of metformin have, in large part, been attributed either to the inhibition of mitochondrial NADH oxidase complex (Complex I in the electron transport chain) or the activation of AMP-activated kinase (AMPK). However, it is becoming increasingly clear that AMPK activation may be critical to alleviate metabolic and energetic stresses associated with tumor progression suggesting that it may, in fact, attenuate the toxicity of metformin instead of promoting it. Here, we demonstrate that AMPK opposes the detrimental effects of mitochondrial complex I inhibition by enhancing glycolysis at the expense of, and in a manner dependent on, pyruvate availability. We also found that metformin forces cells to rewire their metabolic grid in a manner that depends on AMPK, with AMPK-competent cells upregulating glycolysis and AMPK-deficient cell resorting to ketogenesis. In fact, while the killing effects of metformin were largely rescued by pyruvate in AMPKcompetent cells, AMPK-deficient cells required instead acetoacetate, a product of fatty acid catabolism indicating a switch from sugar to fatty acid metabolism as a central resource for ATP production in these cells. In summary, our results indicate that AMPK activation is not responsible for metformin anticancer activity and may instead alleviate energetic stress by activating glycolysis. (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.) |
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| معلومات مُعتمدة: | R01HL142152 U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI); R01 ES028149 United States ES NIEHS NIH HHS; R01 HL153397 United States HL NHLBI NIH HHS; R01 AI131267 United States AI NIAID NIH HHS; R01 CA216882 United States CA NCI NIH HHS |
| المشرفين على المادة: | 9100L32L2N (Metformin) EC 2.7.11.31 (AMP-Activated Protein Kinases) |
| تواريخ الأحداث: | Date Created: 20210722 Date Completed: 20211229 Latest Revision: 20230205 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC8669831 |
| DOI: | 10.1038/s41388-021-01943-x |
| PMID: | 34290400 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 1476-5594 |
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| DOI: | 10.1038/s41388-021-01943-x |