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Severe consequences of a high-lipid diet include hydrogen sulfide dysfunction and enhanced aggression in glioblastoma
Daniel J. Silver, … , Christopher Hine, Justin D. Lathia
Daniel J. Silver, … , Christopher Hine, Justin D. Lathia
Published July 13, 2021
Citation Information: J Clin Invest. 2021;131(17):e138276. https://doi.org/10.1172/JCI138276.
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Research Article Oncology

Severe consequences of a high-lipid diet include hydrogen sulfide dysfunction and enhanced aggression in glioblastoma

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Abstract

Glioblastoma (GBM) remains among the deadliest of human malignancies, and the emergence of the cancer stem cell (CSC) phenotype represents a major challenge to durable treatment response. Because the environmental and lifestyle factors that impact CSC populations are not clear, we sought to understand the consequences of diet on CSC enrichment. We evaluated disease progression in mice fed an obesity-inducing high-fat diet (HFD) versus a low-fat, control diet. HFD resulted in hyperaggressive disease accompanied by CSC enrichment and shortened survival. HFD drove intracerebral accumulation of saturated fats, which inhibited the production of the cysteine metabolite and gasotransmitter, hydrogen sulfide (H2S). H2S functions principally through protein S-sulfhydration and regulates multiple programs, including bioenergetics and metabolism. Inhibition of H2S increased proliferation and chemotherapy resistance, whereas treatment with H2S donors led to death of cultured GBM cells and stasis of GBM tumors in vivo. Syngeneic GBM models and GBM patient specimens present an overall reduction in protein S-sulfhydration, primarily associated with proteins regulating cellular metabolism. These findings provide clear evidence that diet-modifiable H2S signaling serves to suppress GBM by restricting metabolic fitness, while its loss triggers CSC enrichment and disease acceleration. Interventions augmenting H2S bioavailability concurrent with GBM standard of care may improve outcomes for patients with GBM.

Authors

Daniel J. Silver, Gustavo A. Roversi, Nazmin Bithi, Sabrina Z. Wang, Katie M. Troike, Chase K.A. Neumann, Grace K. Ahuja, Ofer Reizes, J. Mark Brown, Christopher Hine, Justin D. Lathia

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Figure 5

Gliomagenesis induces significant loss in H2S synthesis and signaling primarily associated with cellular metabolism.

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Gliomagenesis induces significant loss in H2S synthesis and signaling pr...
(A) Analysis of H2S production confirms that human GBM tumors produce a lower amount of H2S than noncancerous control brain tissues. Each well contains brain or tumor tissue homogenate from separate biopsy specimens. P values determined by unpaired t test. (B) Volcano plot representing the LC-MS S-sulfhydration analysis reveals striking deficits in the posttranslational H2S signaling profile of human GBM as compared with noncancerous human brain tissue. (C) KEGG pathway analysis of the proteins that have undergone S-sulfhydration loss in the context of GBM identifies a broad-spectrum molecular reprogramming centered on GBM tumor cell metabolism. Inhibition of H2S synthesis drives cultured GBM cells into a state of enhanced cellular energetics. Long-term culture of the syngeneic GBM models KR158 and CT2A with PAG resulted in increased metabolic fitness and cellular energetics when compared with vehicle control conditions. Enhanced metabolism was evident at baseline and persisted after introduction of the fatty acid substrate oleic acid. Assessments of cellular metabolism and energetics were based on mitochondrial respiration (D and F), measured by the rate of oxygen consumption (OCR) as well as cellular glycolysis (E and G), measured by the extracellular acidification rate (ECAR). Seahorse Analyzer experiments were conducted in biological triplicate. P values determined by 2-way ANOVA.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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