Fasting reduces glucose levels and protects mice against chemotoxicity, yet drugs that promote hyperglycemia are widely used in cancer treatment. Here, we show that dexamethasone (Dexa) and rapamycin (Rapa), commonly administered to cancer patients, elevate glucose and sensitize cardiomyocytes and mice to the cancer drug doxorubicin (DXR). Such toxicity can be reversed by reducing circulating glucose levels by fasting or insulin. Furthermore, glucose injections alone reversed the fasting-dependent protection against DXR in mice, indicating that elevated glucose mediates, at least in part, the sensitizing effects of rapamycin and dexamethasone. In yeast, glucose activates protein kinase A (PKA) to accelerate aging by inhibiting transcription factors Msn2/4. Here, we show that fasting or glucose restriction (GR) regulate PKA and AMP-activated protein kinase (AMPK) to protect against DXR in part by activating the mammalian Msn2/4 ortholog early growth response protein 1 (EGR1). Increased expression of the EGR1-regulated cardioprotective peptides atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in heart tissue may also contribute to DXR resistance. Our findings suggest the existence of a glucose-PKA pathway that inactivates conserved zinc finger stress-resistance transcription factors to sensitize cells to toxins conserved from yeast to mammals. Our findings also describe a toxic role for drugs widely used in cancer treatment that promote hyperglycemia and identify dietary interventions that reverse these effects.

Center for Translational Medicine St Anne's University Hospital Brno Czech Republic

Centro Studi Fegato Liver Research Center Fondazione Italiana Fegato Trieste Italy

Department of Experimental Biomedicine and Clinical Neuroscience University of Palermo Palermo Italy

Euro Mediterranean Institute of Science and Technology Palermo Italy

IFOM FIRC Institute of Molecular Oncology Milano Italy

Institute for Liver and Digestive Health Royal Free Hospital University College London London United Kingdom

Longevity Institute Leonard Davis School of Gerontology and Department of Biological Sciences University of Southern California Los Angeles California United States of America

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PLoS Biol. 2017 May 1;15(5):e1002603. doi: 10.1371/journal.pbio.1002603. PubMed

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Takemura G, Fujiwara H. Doxorubicin-induced cardiomyopathy from the cardiotoxic mechanisms to management. Progress in cardiovascular diseases. 2007. Mar-Apr;49(5):330–52. 10.1016/j.pcad.2006.10.002 PubMed DOI

Tucker MA, Jones PH, Boice JD Jr., Robison LL, Stone BJ, Stovall M, et al. Therapeutic radiation at a young age is linked to secondary thyroid cancer. The Late Effects Study Group. Cancer research. 1991. June 1;51(11):2885–8. PubMed

Schneider U, Kaser-Hotz B. A simple dose-response relationship for modeling secondary cancer incidence after radiotherapy. Zeitschrift fur medizinische Physik. 2005;15(1):31–7. PubMed

Bhatia S, Yasui Y, Robison LL, Birch JM, Bogue MK, Diller L, et al. High risk of subsequent neoplasms continues with extended follow-up of childhood Hodgkin's disease: report from the Late Effects Study Group. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2003. December 1;21(23):4386–94. PubMed

Steinherz LJ, Steinherz PG, Tan CT, Heller G, Murphy ML. Cardiac toxicity 4 to 20 years after completing anthracycline therapy. Jama. 1991. September 25;266(12):1672–7. PubMed

Zhang S, Liu X, Bawa-Khalfe T, Lu LS, Lyu YL, Liu LF, et al. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nature medicine. 2012. November;18(11):1639–42. 10.1038/nm.2919 PubMed DOI

Herrstedt J, Aapro MS, Roila F, Kataja VV. ESMO Minimum Clinical Recommendations for prophylaxis of chemotherapy-induced nausea and vomiting (NV). Annals of oncology: official journal of the European Society for Medical Oncology/ESMO. 2005;16 Suppl 1:i77–9. PubMed

Jordan K, Kasper C, Schmoll HJ. Chemotherapy-induced nausea and vomiting: current and new standards in the antiemetic prophylaxis and treatment. Eur J Cancer. 2005. January;41(2):199–205. 10.1016/j.ejca.2004.09.026 PubMed DOI

Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M, et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. The New England journal of medicine. 2014. September 4;371(10):906–17. 10.1056/NEJMoa1402551 PubMed DOI

Lendvai N, Hilden P, Devlin S, Landau H, Hassoun H, Lesokhin AM, et al. A phase 2 single-center study of carfilzomib 56 mg/m2 with or without low-dose dexamethasone in relapsed multiple myeloma. Blood. 2014. August 7;124(6):899–906. 10.1182/blood-2014-02-556308 PubMed DOI PMC

Gisselbrecht C. Should We Replace Dexamethasone, Cytarabine, and Cisplatin for Relapsed Lymphoma? Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2014. September 29;32(31):3472–3. PubMed

Samuels AL, Beesley AH, Yadav BD, Papa RA, Sutton R, Anderson D, et al. A pre-clinical model of resistance to induction therapy in pediatric acute lymphoblastic leukemia. Blood cancer journal. 2014;4:e232 10.1038/bcj.2014.52 PubMed DOI PMC

Lukins MB, Manninen PH. Hyperglycemia in patients administered dexamethasone for craniotomy. Anesthesia and analgesia. 2005. April;100(4):1129–33. 10.1213/01.ANE.0000146943.45445.55 PubMed DOI

Bostrom B, Uppal P, Chu J, Messinger Y, Gandrud L, McEvoy R. Safety and efficacy of metformin for therapy-induced hyperglycemia in children with acute lymphoblastic leukemia. Journal of pediatric hematology/oncology. 2013. October;35(7):504–8. 10.1097/MPH.0b013e31829cdeba PubMed DOI

Leib SL, Heimgartner C, Bifrare YD, Loeffler JM, Taauber MG. Dexamethasone aggravates hippocampal apoptosis and learning deficiency in pneumococcal meningitis in infant rats. Pediatric research. 2003. September;54(3):353–7. 10.1203/01.PDR.0000079185.67878.72 PubMed DOI

Poungvarin N, Bhoopat W, Viriyavejakul A, Rodprasert P, Buranasiri P, Sukondhabhant S, et al. Effects of dexamethasone in primary supratentorial intracerebral hemorrhage. The New England journal of medicine. 1987. May 14;316(20):1229–33. 10.1056/NEJM198705143162001 PubMed DOI

Seto B. Rapamycin and mTOR: a serendipitous discovery and implications for breast cancer. Clinical and translational medicine. 2012;1(1):29 10.1186/2001-1326-1-29 PubMed DOI PMC

Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008. August 9;372(9637):449–56. 10.1016/S0140-6736(08)61039-9 PubMed DOI

Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. The New England journal of medicine. 2007. May 31;356(22):2271–81. 10.1056/NEJMoa066838 PubMed DOI

Busaidy NL, Farooki A, Dowlati A, Perentesis JP, Dancey JE, Doyle LA, et al. Management of metabolic effects associated with anticancer agents targeting the PI3K-Akt-mTOR pathway. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2012. August 10;30(23):2919–28. PubMed PMC

Houde VP, Brule S, Festuccia WT, Blanchard PG, Bellmann K, Deshaies Y, et al. Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue. Diabetes. 2010. June;59(6):1338–48. 10.2337/db09-1324 PubMed DOI PMC

Longo VD, Mattson MP. Fasting: Molecular Mechanisms and Clinical Applications. Cell metabolism. 2014. February 4;19(2):181–92. 10.1016/j.cmet.2013.12.008 PubMed DOI PMC

Fontana L, Partridge L, Longo VD. Extending healthy life span—from yeast to humans. Science. 2010. April 16;328(5976):321–6. 10.1126/science.1172539 PubMed DOI PMC

Brandhorst S, Choi IY, Wei M, Cheng CW, Sedrakyan S, Navarrete G, et al. A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan. Cell metabolism. 2015. July 7;22(1):86–99. 10.1016/j.cmet.2015.05.012 PubMed DOI PMC

Crouthamel MC, Kahana JA, Korenchuk S, Zhang SY, Sundaresan G, Eberwein DJ, et al. Mechanism and management of AKT inhibitor-induced hyperglycemia. Clinical cancer research: an official journal of the American Association for Cancer Research. 2009. January 1;15(1):217–25. PubMed

Di Biase S, Lee C, Brandhorst S, Manes B, Buono R, Cheng CW, et al. Fasting-Mimicking Diet Reduces HO-1 to Promote T Cell-Mediated Tumor Cytotoxicity. Cancer cell. 2016. July 11;30(1):136–46. 10.1016/j.ccell.2016.06.005 PubMed DOI PMC

Josefsen K, Sorensen LR, Buschard K, Birkenbach M. Glucose induces early growth response gene (Egr-1) expression in pancreatic beta cells. Diabetologia. 1999. February;42(2):195–203. 10.1007/s001250051139 PubMed DOI

Raffaghello L, Lee C, Safdie FM, Wei M, Madia F, Bianchi G, et al. Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy. Proceedings of the National Academy of Sciences of the United States of America. 2008. June 17;105(24):8215–20. 10.1073/pnas.0708100105 PubMed DOI PMC

Wei M, Fabrizio P, Hu J, Ge H, Cheng C, Li L, et al. Life span extension by calorie restriction depends on Rim15 and transcription factors downstream of Ras/PKA, Tor, and Sch9. PLoS Genet. 2008. January;4(1):e13 10.1371/journal.pgen.0040013 PubMed DOI PMC

Estruch F, Carlson M. Two homologous zinc finger genes identified by multicopy suppression in a SNF1 protein kinase mutant of Saccharomyces cerevisiae. Molecular and cellular biology. 1993. July;13(7):3872–81. PubMed PMC

Yu J, Zhang SS, Saito K, Williams S, Arimura Y, Ma Y, et al. PTEN regulation by Akt-EGR1-ARF-PTEN axis. The EMBO journal. 2009. January 7;28(1):21–33. 10.1038/emboj.2008.238 PubMed DOI PMC

Sukhatme VP, Cao XM, Chang LC, Tsai-Morris CH, Stamenkovich D, Ferreira PC, et al. A zinc finger-encoding gene coregulated with c-fos during growth and differentiation, and after cellular depolarization. Cell. 1988. April 8;53(1):37–43. PubMed

Baron V, Adamson ED, Calogero A, Ragona G, Mercola D. The transcription factor Egr1 is a direct regulator of multiple tumor suppressors including TGFbeta1, PTEN, p53, and fibronectin. Cancer gene therapy. 2006. February;13(2):115–24. 10.1038/sj.cgt.7700896 PubMed DOI PMC

Berasi SP, Huard C, Li D, Shih HH, Sun Y, Zhong W, et al. Inhibition of gluconeogenesis through transcriptional activation of EGR1 and DUSP4 by AMP-activated kinase. The Journal of biological chemistry. 2006. September 15;281(37):27167–77. 10.1074/jbc.M602416200 PubMed DOI

Andrade J, Quinn J, Becker RZ, Shupnik MA. AMP-activated protein kinase is a key intermediary in GnRH-stimulated LHbeta gene transcription. Mol Endocrinol. 2013. May;27(5):828–39. 10.1210/me.2012-1323 PubMed DOI PMC

Hurley RL, Barre LK, Wood SD, Anderson KA, Kemp BE, Means AR, et al. Regulation of AMP-activated protein kinase by multisite phosphorylation in response to agents that elevate cellular cAMP. The Journal of biological chemistry. 2006. December 1;281(48):36662–72. 10.1074/jbc.M606676200 PubMed DOI

Djouder N, Tuerk RD, Suter M, Salvioni P, Thali RF, Scholz R, et al. PKA phosphorylates and inactivates AMPKalpha to promote efficient lipolysis. The EMBO journal. 2010. January 20;29(2):469–81. 10.1038/emboj.2009.339 PubMed DOI PMC

Iwata T, Taniguchi H, Kuwajima M, Taniguchi T, Okuda Y, Sukeno A, et al. The action of D-dopachrome tautomerase as an adipokine in adipocyte lipid metabolism. PLoS ONE. 2012;7(3):e33402 10.1371/journal.pone.0033402 PubMed DOI PMC

Lee C, Safdie FM, Raffaghello L, Wei M, Madia F, Parrella E, et al. Reduced levels of IGF-I mediate differential protection of normal and cancer cells in response to fasting and improve chemotherapeutic index. Cancer research. 2010. February 15;70(4):1564–72. 10.1158/0008-5472.CAN-09-3228 PubMed DOI PMC

Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science. 2012. March 30;335(6076):1638–43. 10.1126/science.1215135 PubMed DOI PMC

Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature. 2006. April 13;440(7086):944–8. 10.1038/nature04634 PubMed DOI

Waldron NH, Jones CA, Gan TJ, Allen TK, Habib AS. Impact of perioperative dexamethasone on postoperative analgesia and side-effects: systematic review and meta-analysis. British journal of anaesthesia. 2013. February;110(2):191–200. 10.1093/bja/aes431 PubMed DOI PMC

Feldman-Billard S, Du Pasquier-Fediaevsky L, Heron E. Hyperglycemia after repeated periocular dexamethasone injections in patients with diabetes. Ophthalmology. 2006. October;113(10):1720–3. 10.1016/j.ophtha.2006.05.023 PubMed DOI

Andrikopoulos S, Blair AR, Deluca N, Fam BC, Proietto J. Evaluating the glucose tolerance test in mice. American journal of physiology Endocrinology and metabolism. 2008. December;295(6):E1323–32. 10.1152/ajpendo.90617.2008 PubMed DOI

Cheng CW, Adams GB, Perin L, Wei M, Zhou X, Lam BS, et al. Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell stem cell. 2014. June 5;14(6):810–23. 10.1016/j.stem.2014.04.014 PubMed DOI PMC

Almeida MQ, Tsang KM, Cheadle C, Watkins T, Grivel JC, Nesterova M, et al. Protein kinase A regulates caspase-1 via Ets-1 in bone stromal cell-derived lesions: a link between cyclic AMP and pro-inflammatory pathways in osteoblast progenitors. Human molecular genetics. 2011. January 1;20(1):165–75. 10.1093/hmg/ddq455 PubMed DOI PMC

Burley DS, Hamid SA, Baxter GF. Cardioprotective actions of peptide hormones in myocardial ischemia. Heart failure reviews. 2007. December;12(3–4):279–91. 10.1007/s10741-007-9029-y PubMed DOI

Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. 2012. April;13(4):251–62. 10.1038/nrm3311 PubMed DOI PMC

Kroemer G, Marino G, Levine B. Autophagy and the integrated stress response. Mol Cell. 2010. October 22;40(2):280–93. 10.1016/j.molcel.2010.09.023 PubMed DOI PMC

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. Proceedings of the National Academy of Sciences of the United States of America. 2004. March 9;101(10):3329–35. 10.1073/pnas.0308061100 PubMed DOI PMC

Bain J, Plater L, Elliott M, Shpiro N, Hastie CJ, McLauchlan H, et al. The selectivity of protein kinase inhibitors: a further update. The Biochemical journal. 2007. December 15;408(3):297–315. 10.1042/BJ20070797 PubMed DOI PMC

Calnan DR, Brunet A. The FoxO code. Oncogene. 2008. April 7;27(16):2276–88. 10.1038/onc.2008.21 PubMed DOI

Pernicova I, Korbonits M. Metformin—mode of action and clinical implications for diabetes and cancer. Nature reviews Endocrinology. 2014. March;10(3):143–56. 10.1038/nrendo.2013.256 PubMed DOI

Wang H, Li M, Rinehart JJ, Zhang R. Pretreatment with dexamethasone increases antitumor activity of carboplatin and gemcitabine in mice bearing human cancer xenografts: in vivo activity, pharmacokinetics, and clinical implications for cancer chemotherapy. Clinical cancer research: an official journal of the American Association for Cancer Research. 2004. March 1;10(5):1633–44. PubMed

Mondesire WH, Jian W, Zhang H, Ensor J, Hung MC, Mills GB, et al. Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells. Clinical cancer research: an official journal of the American Association for Cancer Research. 2004. October 15;10(20):7031–42. PubMed

Weiser MA, Cabanillas ME, Konopleva M, Thomas DA, Pierce SA, Escalante CP, et al. Relation between the duration of remission and hyperglycemia during induction chemotherapy for acute lymphocytic leukemia with a hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone/methotrexate-cytarabine regimen. Cancer. 2004. March 15;100(6):1179–85. 10.1002/cncr.20071 PubMed DOI

Xie Z, Lau K, Eby B, Lozano P, He C, Pennington B, et al. Improvement of cardiac functions by chronic metformin treatment is associated with enhanced cardiac autophagy in diabetic OVE26 mice. Diabetes. 2011. June;60(6):1770–8. 10.2337/db10-0351 PubMed DOI PMC

Porntadavity S, Xu Y, Kiningham K, Rangnekar VM, Prachayasittikul V, St Clair DK. TPA-activated transcription of the human MnSOD gene: role of transcription factors Sp-1 and Egr-1. DNA and cell biology. 2001. August;20(8):473–81. 10.1089/104454901316976109 PubMed DOI

Sadeh A, Movshovich N, Volokh M, Gheber L, Aharoni A. Fine-tuning of the Msn2/4-mediated yeast stress responses as revealed by systematic deletion of Msn2/4 partners. Molecular biology of the cell. 2011. September;22(17):3127–38. 10.1091/mbc.E10-12-1007 PubMed DOI PMC

Kops GJ, Dansen TB, Polderman PE, Saarloos I, Wirtz KW, Coffer PJ, et al. Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature. 2002. September 19;419(6904):316–21. 10.1038/nature01036 PubMed DOI

Conklin KA. Dietary antioxidants during cancer chemotherapy: impact on chemotherapeutic effectiveness and development of side effects. Nutrition and cancer. 2000;37(1):1–18. 10.1207/S15327914NC3701_1 PubMed DOI

Divakaruni AS, Brand MD. The regulation and physiology of mitochondrial proton leak. Physiology (Bethesda). 2011. June;26(3):192–205. PubMed

Kapoun AM, Liang F, O'Young G, Damm DL, Quon D, White RT, et al. B-type natriuretic peptide exerts broad functional opposition to transforming growth factor-beta in primary human cardiac fibroblasts: fibrosis, myofibroblast conversion, proliferation, and inflammation. Circulation research. 2004. March 5;94(4):453–61. 10.1161/01.RES.0000117070.86556.9F PubMed DOI

Lin X, Hanze J, Heese F, Sodmann R, Lang RE. Gene expression of natriuretic peptide receptors in myocardial cells. Circulation research. 1995. October;77(4):750–8. PubMed

Nishikimi T, Maeda N, Matsuoka H. The role of natriuretic peptides in cardioprotection. Cardiovascular research. 2006. February 1;69(2):318–28. 10.1016/j.cardiores.2005.10.001 PubMed DOI

Tokudome T, Horio T, Kishimoto I, Soeki T, Mori K, Kawano Y, et al. Calcineurin-nuclear factor of activated T cells pathway-dependent cardiac remodeling in mice deficient in guanylyl cyclase A, a receptor for atrial and brain natriuretic peptides. Circulation. 2005. June 14;111(23):3095–104. 10.1161/CIRCULATIONAHA.104.510594 PubMed DOI

Tokudome T, Kishimoto I, Horio T, Arai Y, Schwenke DO, Hino J, et al. Regulator of G-protein signaling subtype 4 mediates antihypertrophic effect of locally secreted natriuretic peptides in the heart. Circulation. 2008. May 06;117(18):2329–39. 10.1161/CIRCULATIONAHA.107.732990 PubMed DOI

Mouli S, Nanayakkara G, AlAlasmari A, Eldoumani H, Fu X, Berlin A, et al. The role of frataxin in doxorubicin-mediated cardiac hypertrophy. American journal of physiology Heart and circulatory physiology. 2015. September;309(5):H844–59. 10.1152/ajpheart.00182.2015 PubMed DOI

Karagiannis TC, Lin AJ, Ververis K, Chang L, Tang MM, Okabe J, et al. Trichostatin A accentuates doxorubicin-induced hypertrophy in cardiac myocytes. Aging. 2010. October;2(10):659–68. 10.18632/aging.100203 PubMed DOI PMC

Lee C, Longo VD. Fasting vs dietary restriction in cellular protection and cancer treatment: from model organisms to patients. Oncogene. 2011. July 28;30(30):3305–16. 10.1038/onc.2011.91 PubMed DOI

Lee C, Raffaghello L, Brandhorst S, Safdie FM, Bianchi G, Martin-Montalvo A, et al. Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Science translational medicine. 2012. March 7;4(124):124ra27 10.1126/scitranslmed.3003293 PubMed DOI PMC

Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999. March 19;96(6):857–68. PubMed

Shim HS, Wei M, Brandhorst S, Longo VD. Starvation promotes REV1 SUMOylation and p53-dependent sensitization of melanoma and breast cancer cells. Cancer research. 2015. March 15;75(6):1056–67. 10.1158/0008-5472.CAN-14-2249 PubMed DOI PMC

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