title: Fasting regulates EGR1 and protects from glucose- and dexamethasone-dependent sensitization to chemotherapy.
abstract: 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.
authors.affiliation: Longevity Institute, Leonard Davis School of Gerontology and Department of Biological Sciences, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Stefano
authors.identifier: 0000-0003-1793-3950
authors.initials: S
authors.lastname: Di Biase
authors.affiliation: Longevity Institute, Leonard Davis School of Gerontology and Department of Biological Sciences, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Hong Seok
authors.initials: HS
authors.lastname: Shim
authors.affiliation: Longevity Institute, Leonard Davis School of Gerontology and Department of Biological Sciences, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Kyung Hwa
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Institute for Liver and Digestive Health, Royal Free Hospital, University College London (UCL), London, United Kingdom.|Center for Translational Medicine (CTM), International Clinical Research Center (ICRC), St. Anne's University Hospital, Brno, Czech Republic.|Centro Studi Fegato (CSF)-Liver Research Center, Fondazione Italiana Fegato, Trieste, Italy.
authors.forename: Manlio
authors.initials: M
authors.lastname: Vinciguerra
authors.affiliation: Euro-Mediterranean Institute of Science and Technology, Palermo, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Rappa
authors.affiliation: Longevity Institute, Leonard Davis School of Gerontology and Department of Biological Sciences, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.affiliation: Longevity Institute, Leonard Davis School of Gerontology and Department of Biological Sciences, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brandhorst
authors.affiliation: Euro-Mediterranean Institute of Science and Technology, Palermo, Italy.|Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo, Palermo, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cappello
authors.affiliation: Longevity Institute, Leonard Davis School of Gerontology and Department of Biological Sciences, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Hamed
authors.initials: H
authors.lastname: Mirzaei
authors.affiliation: Longevity Institute, Leonard Davis School of Gerontology and Department of Biological Sciences, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Changhan
authors.initials: C
authors.lastname: Lee
authors.affiliation: Longevity Institute, Leonard Davis School of Gerontology and Department of Biological Sciences, University of Southern California, Los Angeles, California, United States of America.|IFOM, FIRC Institute of Molecular Oncology, Milano, Italy.
authors.forename: Valter D
authors.initials: VD
authors.lastname: Longo
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D054715:Cardiotoxins / Q000633:toxicity; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D004032:Diet; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D005215:Fasting / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000494:pharmacology*; D006943:Hyperglycemia / Q000473:pathology; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D054715:Cardiotoxins; D051766:Early Growth Response Protein 1; D020097:Natriuretic Peptide, Brain; D003907:Dexamethasone; D009320:Atrial Natriuretic Factor; D008687:Metformin; D017868:Cyclic AMP-Dependent Protein Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose