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, 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 |
أسماء مطبوعة: | Publication: <2002->: Basingstoke : Nature Publishing Group Original Publication: Basingstoke, Hampshire, UK : Scientific & Medical Division, MacMillan Press, c1987- |
مواضيع طبية MeSH: | Metformin*/pharmacology , Energy Metabolism*/drug effects , AMP-Activated Protein Kinases*/metabolism , Glycolysis*/drug effects , Carbohydrate Metabolism*/drug effects, Humans ; Cell Line, Tumor ; Electron Transport Complex I/metabolism ; Pyruvic Acid/metabolism ; Ketone Bodies/metabolism ; Mitochondria/metabolism ; Mitochondria/drug effects ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Neoplasms/pathology |
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.) |
References: | Flory J, Lipska K. Metformin in 2019. JAMA. 2019;321:1926–7. (PMID: 10.1001/jama.2019.3805) Fryer LG, Parbu-Patel A, Carling D. The Anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. J Biol Chem. 2002;277:25226–32. (PMID: 10.1074/jbc.M202489200) Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108:1167–74. (PMID: 10.1172/JCI13505) Kurth-Kraczek EJ, Hirshman MF, Goodyear LJ, Winder WW. 5’ AMP-activated protein kinase activation causes GLUT4 translocation in skeletal muscle. Diabetes. 1999;48:1667–71. (PMID: 10.2337/diabetes.48.8.1667) Cazzaniga M, Bonanni B, Guerrieri-Gonzaga A, Decensi A. Is it time to test metformin in breast cancer clinical trials? Cancer Epidemiol Biomark Prev. 2009;18:701–5. (PMID: 10.1158/1055-9965.EPI-08-0871) Ferreira GD, Germeyer A, de Barros Machado A, do Nascimento TL, Strowitzki T, Brum IS, et al. Metformin modulates PI3K and GLUT4 expression and Akt/PKB phosphorylation in human endometrial stromal cells after stimulation with androgen and insulin. Eur J Obstet Gynecol Reprod Biol. 2014;175:157–62. (PMID: 10.1016/j.ejogrb.2014.01.009) Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care. 2009;32:1620–5. (PMID: 10.2337/dc08-2175) Bo S, Benso A, Durazzo M, Ghigo E. Does use of metformin protect against cancer in Type 2 diabetes mellitus? J Endocrinol Invest. 2012;35:231–5. (PMID: 10.1007/BF03345423) Zhao H, Li T, Wang K, Zhao F, Chen J, Xu G, et al. AMPK-mediated activation of MCU stimulates mitochondrial Ca(2+) entry to promote mitotic progression. Nat Cell Biol. 2019;21:476–86. (PMID: 10.1038/s41556-019-0296-3) Hardie DG, Schaffer BE, Brunet A. AMPK: an energy-sensing pathway with multiple inputs and outputs. Trends Cell Biol. 2016;26:190–201. (PMID: 10.1016/j.tcb.2015.10.013) Tennakoon JB, Shi Y, Han JJ, Tsouko E, White MA, Burns AR, et al. Androgens regulate prostate cancer cell growth via an AMPK-PGC-1alpha-mediated metabolic switch. Oncogene. 2014;33:5251–61. (PMID: 10.1038/onc.2013.463) Eichner LJ, Brun SN, Herzig S, Young NP, Curtis SD, Shackelford DB, et al. Genetic analysis reveals AMPK is required to support tumor growth in murine Kras-dependent lung cancer models. Cell Metab. 2019;29:285–302. e287. (PMID: 10.1016/j.cmet.2018.10.005) Hart PC, Mao M, de Abreu AL, Ansenberger-Fricano K, Ekoue DN, Ganini D, et al. MnSOD upregulation sustains the Warburg effect via mitochondrial ROS and AMPK-dependent signalling in cancer. Nat Commun. 2015;6:6053. (PMID: 10.1038/ncomms7053) Feng Y, Ke C, Tang Q, Dong H, Zheng X, Lin W, et al. Metformin promotes autophagy and apoptosis in esophageal squamous cell carcinoma by downregulating Stat3 signaling. Cell Death Dis. 2014;5:e1088. (PMID: 10.1038/cddis.2014.59) Menendez JA, Oliveras-Ferraros C, Cufi S, Corominas-Faja B, Joven J, Martin-Castillo B, et al. Metformin is synthetically lethal with glucose withdrawal in cancer cells. Cell Cycle. 2012;11:2782–92. (PMID: 10.4161/cc.20948) Cheong JH, Park ES, Liang J, Dennison JB, Tsavachidou D, Nguyen-Charles C, et al. Dual inhibition of tumor energy pathway by 2-deoxyglucose and metformin is effective against a broad spectrum of preclinical cancer models. Mol Cancer Ther. 2011;10:2350–62. (PMID: 10.1158/1535-7163.MCT-11-0497) Ferretti AC, Hidalgo F, Tonucci FM, Almada E, Pariani A, Larocca MC, et al. Metformin and glucose starvation decrease the migratory ability of hepatocellular carcinoma cells: targeting AMPK activation to control migration. Sci Rep. 2019;9:2815. (PMID: 10.1038/s41598-019-39556-w) King MP, Attardi G. Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science. 1989;246:500–3. (PMID: 10.1126/science.2814477) Almeida A, Moncada S, Bolanos JP. Nitric oxide switches on glycolysis through the AMP protein kinase and 6-phosphofructo-2-kinase pathway. Nat Cell Biol. 2004;6:45–51. (PMID: 10.1038/ncb1080) Gutman M, Singer TP, Beinert H, Casida JE. Reaction sites of rotenone, piericidin A, and amytal in relation to the nonheme iron components of NADH dehydrogenase. Proc Natl Acad Sci USA. 1970;65:763–70. (PMID: 10.1073/pnas.65.3.763) Djavadi-Ohaniance L, Hatefi H. Oxidation of NADPH by submitochondrial particles from beef heart in complete absence of transhydrogenase activity from NADPH to NAD. J Biol Chem. 1975;250:9397–403. (PMID: 10.1016/S0021-9258(19)40657-1) Xu J, Ji J, Yan XH. Cross-talk between AMPK and mTOR in regulating energy balance. Crit Rev Food Sci Nutr. 2012;52:373–81. (PMID: 10.1080/10408398.2010.500245) Spinelli JB, Yoon H, Ringel AE, Jeanfavre S, Clish CB, Haigis MC. Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass. Science. 2017;358:941–6. (PMID: 10.1126/science.aam9305) Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA, et al. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci USA. 2004;101:3329–35. (PMID: 10.1073/pnas.0308061100) Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y, et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell. 2005;18:283–93. (PMID: 10.1016/j.molcel.2005.03.027) |
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) EC 7.1.1.2 (Electron Transport Complex I) 8558G7RUTR (Pyruvic Acid) 0 (Ketone Bodies) |
تواريخ الأحداث: | Date Created: 20210722 Date Completed: 20240725 Latest Revision: 20240729 |
رمز التحديث: | 20240729 |
مُعرف محوري في PubMed: | PMC8669831 |
DOI: | 10.1038/s41388-021-01943-x |
PMID: | 34290400 |
قاعدة البيانات: | MEDLINE |
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