TMET-29. Sulfide oxidation activity is essential for mitochondrial respiration and growth in glioblastoma

Metabolic reprogramming enables glioblastoma cells to thrive under adverse conditions by utilizing available fuel sources. While previously explored for its tumor suppressive activities in glioblastoma, hydrogen sulfide (H2S), a gaseous signaling molecule can both inhibit the electron transport chain at complex IV and act as an electron donor by reducing coenzyme Q. The contradictory nature of H2S depends upon the ability of cells to increase sulfide oxidation. Mitochondrial sulfide oxidation eliminates H2S through a series of redox reactions, beginning with two key enzymes, sulfide quinone oxidoreductase (SQOR) and persulfide dioxygenase (ETHE1). Through examination of patient tumor transcriptional data, we identified SQOR and ETHE1 to inversely correlate with patient prognosis, representing a potential driver of glioblastoma progression. Using patient derived glioblastoma cells, we observed increased sulfide oxidation capabilities in response to exogenous H2S. As sulfide oxidation increased in response to exogenous H2S, we examined how manipulating the rate limiting step catalyzed by SQOR impacts tumor growth in vivo. Knockdown of SQOR in murine glioblastoma models led to a robust survival extension. Corresponding in vitro experiments performed with genetic or pharmacological perturbation of SQOR in human glioblastoma cells showed increased intracellular H2S accumulation measured by flow cytometry. The increase in H2S accumulation, lead to decreased self-renewal and proliferation. These observations were driven by a decrease in mitochondrial respiration and ATP production measured via Seahorse assay, with an increased reliance upon glycolytic activity, and an inability to mobilize lipid reserves. Conversely, SQOR overexpression produced the opposite result in all experimental systems. These findings demonstrate how amplification of sulfide oxidation enables glioblastoma cells to shunt H2S into mitochondrial respiration. Targeting sulfide oxidation therefore presents as an intriguing means of disrupting oxidative phosphorylation and suppressing lipid metabolism in highly adaptive glioblastoma stem cells which can be combined with glycolysis inhibitors to suppress tumor growth.