Ferrer M, Mourikis N, Davidson EE, Kleeman SO, Zaccaria M, Habel J, Rubino R, Gao Q, Flint TR, Young L, Connell CM, Lukey MJ, Goncalves MD, White EP, Venkitaraman AR, Janowitz T.
Affiliations
- 1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; MRC Cancer Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.
- 2Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
- 3University College London, London WC1E 6BT, UK.
- 4Department of Oncology, CRUK Cambridge Institute, Cambridge Biomedical Campus, Cambridge CB2 0RE, UK.
- 5Division of Endocrinology, Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA.
- 6Department of Molecular Biology and Biochemistry, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA; Ludwig Princeton Branch, Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ 08544, USA.
- 7MRC Cancer Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK; Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore; Institute for Molecular & Cell Biology, Agency for Science, Technology and Research (A∗STAR), Singapore 138648, Singapore.
- 8Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Northwell Health Cancer Institute, Northwell Health, New Hyde Park, NY 11042, USA. Electronic address: janowitz@cshl.edu.
Abstract
Glucose dependency of cancer cells can be targeted with a high-fat, low-carbohydrate ketogenic diet (KD). However, in IL-6-producing cancers, suppression of the hepatic ketogenic potential hinders the utilization of KD as energy for the organism. In IL-6-associated murine models of cancer cachexia, we describe delayed tumor growth but accelerated cachexia onset and shortened survival in mice fed KD. Mechanistically, this uncoupling is a consequence of the biochemical interaction of two NADPH-dependent pathways. Within the tumor, increased lipid peroxidation and, consequently, saturation of the glutathione (GSH) system lead to the ferroptotic death of cancer cells. Systemically, redox imbalance and NADPH depletion impair corticosterone biosynthesis. Administration of dexamethasone, a potent glucocorticoid, increases food intake, normalizes glucose levels and utilization of nutritional substrates, delays cachexia onset, and extends the survival of tumor-bearing mice fed KD while preserving reduced tumor growth. Our study emphasizes the need to investigate the effects of systemic interventions on both the tumor and the host to accurately assess therapeutic potential. These findings may be relevant to clinical research efforts that investigate nutritional interventions such as KD in patients with cancer.
PMID: 37311455 DOI: 10.1016/j.cmet.2023.05.008