Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia

Ferrer, Miriam, Mourikis, Nicholas, Davidson, Emma E, Kleeman, Sam O, Zaccaria, Marta, Habel, Jill, Rubino, Rachel, Gao, Qing, Flint, Thomas R, Young, Lisa, Connell, Claire M, Lukey, Michael J, Goncalves, Marcus D, White, Eileen P, Venkitaraman, Ashok R, Janowitz, Tobias (July 2023) Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia. Cell Metabolism, 35 (7). 1147-1162.e7. ISSN 1550-4131

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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.

Item Type: Paper
Subjects: diseases & disorders > cancer
diseases & disorders
diseases & disorders > neoplasms
diseases & disorders > nutritional and metabolic diseases
organism description > animal
diseases & disorders > nutritional and metabolic diseases > cachexia
organism description > animal > mammal > rodent > mouse
organism description > animal > mammal > rodent
CSHL Authors:
Communities: CSHL Cancer Center Program
CSHL Cancer Center Program > Cancer Genetics and Genomics Program
CSHL Cancer Center Program > Cellular Communication in Cancer Program
CSHL Cancer Center Shared Resources > Animal Services
CSHL Cancer Center Shared Resources > Animal Tissue and Imaging Service
CSHL Cancer Center Shared Resources > Flow Cytometry Service
School of Biological Sciences > Publications
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 11 July 2023
Date Deposited: 21 Sep 2023 19:52
Last Modified: 29 Feb 2024 17:07
Related URLs:
URI: https://repository.cshl.edu/id/eprint/40958

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