한빛사논문
- 조회1,173
Abstract
Stefano Di Biase1†, Hong Seok Shim1†, Kyung Hwa Kim1†, Manlio Vinciguerra2,3,4, Francesca Rappa5, Min Wei1, Sebastian Brandhorst1, Francesco Cappello5,6, Hamed Mirzaei1, Changhan Lee1, Valter D. Longo1,7*
1 Longevity Institute, Leonard Davis School of Gerontology and Department of Biological Sciences, University of Southern California, Los Angeles, California, United States of America, 2 Institute for Liver and Digestive Health, Royal Free Hospital, University College London (UCL), London, United Kingdom, 3 Center for Translational Medicine (CTM), International Clinical Research Center (ICRC), St. Anne's University Hospital, Brno, Czech Republic, 4 Centro Studi Fegato (CSF)-Liver Research Center, Fondazione Italiana Fegato, Trieste, Italy, 5 Euro-Mediterranean Institute of Science and Technology, Palermo, Italy, 6 Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo, Palermo, Italy, 7 IFOM, FIRC Institute of Molecular Oncology, Milano, Italy
† These authors contributed equally to this work.
* Corresponding author
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.
논문정보
- Research article
- 2017년 03월 (BRIC 등록일 2017-04-04)
- 국외 연구진
- 생명과학 > 분자생물학
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