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:	Mourikis, Nicholas Kleeman, Sam Habel, Jill Rubino, Rachel Gao, Qing Lukey, Michael Janowitz, Tobias Ferrer, Miriam Davidson, Emma
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:	Publisher
URI:	https://repository.cshl.edu/id/eprint/40958

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