Fasting regulates EGR1 and protects from glucose- and dexamethasone-dependent sensitization to chemotherapy

PLoS Biol. 2017 Mar 30;15(3):e2001951. doi: 10.1371/journal.pbio.2001951. eCollection 2017 Mar.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Atrial Natriuretic Factor / metabolism
  • Cardiotoxins / toxicity
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Cytoprotection / drug effects
  • Dexamethasone / pharmacology*
  • Diet
  • Early Growth Response Protein 1 / metabolism*
  • Fasting / metabolism*
  • Female
  • Glucose / pharmacology*
  • Hyperglycemia / pathology
  • Metformin / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Natriuretic Peptide, Brain / metabolism
  • Stress, Physiological / drug effects
  • Time Factors

Substances

  • Antineoplastic Agents
  • Cardiotoxins
  • Early Growth Response Protein 1
  • Natriuretic Peptide, Brain
  • Dexamethasone
  • Atrial Natriuretic Factor
  • Metformin
  • Cyclic AMP-Dependent Protein Kinases
  • AMP-Activated Protein Kinases
  • Glucose

Grant support

National Program of Sustainability II (MEYS CR) (grant number LQ1605).Received by MV. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. FNUSA-ICRC http://www.fnusa-icrc.org/en/ (grant number CZ.1.05/1.1.00/02.0123).Received by MV. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NIH/NIA https://www.nia.nih.gov/research/funding (grant number AG034906).Received by VDL. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NIH/NIA https://www.nia.nih.gov/research/funding (grant number AG20642).Received by VDL. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.