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

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

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 3

HFD and gliomagenesis inhibit H2S production.

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HFD and gliomagenesis inhibit H2S production. (A) Schematic detailing th...
(A) Schematic detailing the generation of H2S as a byproduct of cysteine metabolism associated with MPST activity and the transsulfuration pathway. (B) H2S production analysis indicates that HFD consumption results in decreased H2S synthesis in the tumors of HFD-fed mice compared with tumors isolated from mice fed a control diet. Each well contains tumor tissue homogenate from separate and distinct experimental animals. P values determined by unpaired t test. (C and D) Human patient data curated by The Cancer Genome Atlas Low-Grade Glioma and GBM data set indicate that patients with GBM present with the lowest average expression of the H2S-generating enzymes CBS and MPST. (E) While the mRNA expression of CGL remained stable across glioma subtype, previously published biochemical analysis confirmed that this enzyme is nonfunctional in the context of GBM.