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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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 6

In vitro and in vivo rescue experimentation links H2S to HFD and validates its tumor suppressive function.

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In vitro and in vivo rescue experimentation links H2S to HFD and validat...
To establish a clear connection between high-fat conditions and H2S, we investigated the protein expression of critical H2S-synthesizing enzymes. Protein analysis (A) confirmed a significant decrease in the protein expression of the H2S-synthesizing enzyme CBS in the context of high-fat feeding. In vitro rescue experiments using 2 concentrations of the H2S donor NaHS were performed while tracking cellular proliferation in real-time in the syngeneic GBM models KR158 (B and C) and CT2A (D and E). For these experiments, standard growth medium was supplemented with the following treatments: 5 μM oleic acid; vehicle; 200 μM or 500 μM NaHS; and 5 μM oleic acid + 200 μM or 500 μM NaHS. All in vitro experiments were conducted in biological triplicate. P values determined by 2-way ANOVA coupled to Dunnett’s multiple comparison test. Last, in vivo rescue (F) was demonstrated using flank hGBM 23 tumors that were established and treated daily with either the chemical H2S donor NaHS or vehicle. For these experiments, treatment was initiated once the flank tumors could be palpated and accurately measured for volume. Protein analysis (G) of endpoint flank tumors confirmed that H2S replacement resulted in marked reduction in the expression of SOX2.