Hydrogen Sulfide Oxidation: Adaptive Changes in Mitochondria of SW480 Colorectal Cancer Cells upon Exposure to Hypoxia

Abstract

Hydrogen sulfide (H2S), a known inhibitor of cytochrome c oxidase (CcOX), plays a key signaling role in human (patho)physiology. H2S is synthesized endogenously and mainly metabolized by a mitochondrial sulfide-oxidizing pathway including sulfide:quinone oxidoreductase (SQR), whereby H2S-derived electrons are injected into the respiratory chain stimulating O2 consumption and ATP synthesis. Under hypoxic conditions, H2S has higher stability and is synthesized at higher levels with protective effects for the cell. Herein, working on SW480 colon cancer cells, we evaluated the effect of hypoxia on the ability of cells to metabolize H2S. The sulfide-oxidizing activity was assessed by high-resolution respirometry, measuring the stimulatory effect of sulfide on rotenone-inhibited cell respiration in the absence or presence of antimycin A. Compared to cells grown under normoxic conditions (air O2), cells exposed for 24 h to hypoxia (1% O2) displayed a 1.3-fold reduction in maximal sulfide-oxidizing activity and 2.7-fold lower basal O2 respiration. Based on citrate synthase activity assays, mitochondria of hypoxia-treated cells were 1.8-fold less abundant and displayed 1.4-fold higher maximal sulfide-oxidizing activity and 2.6-fold enrichment in SQR as evaluated by immunoblotting. We speculate that under hypoxic conditions mitochondria undergo these adaptive changes to protect cell respiration from H2S poisoning.

N-Acetylcysteine Serves as Substrate of 3-Mercaptopyruvate Sulfurtransferase and Stimulates Sulfide Metabolism in Colon Cancer Cells

“…Recently, Libiad and colleagues reported increased SQR expression in colon cancer patient samples relatively to the surrounding normal tissue, and found a correlation between increased SQR expression and the degree of malignancy in human colorectal cancer tissues and cell lines [30]. Moreover, in the SW480 colorectal cancer cell line, an increase in mitochondrial levels of SQR has been proposed to afford an adaptive response upon exposure to hypoxia, a common feature within the tumor microenvironment [43].…”

Emerging pharmacological tools to control hydrogen sulfide signaling in critical illness

“…Cardinal features of ethylmalonic encephalopathy are associated with extreme elevation of circulating and tissue H 2 S levels [19]. H 2 S accumulates in hypoxic conditions due to the inhibition of SOU activity and decreased spontaneous oxidation [49,83,84]. CBS and CSE could translocate into mitochondria in hypoxic condition as described above.…”

Cysteine metabolic circuitries: druggable targets in cancer

“…109,153 Accordingly, exposure of SW480 colorectal cancer cells to hypoxia resulted in an enrichment in mitochondria of SQR protein levels and H 2 S detoxification activity. 154 Besides the bioenergetics stimulation, the antioxidant nature of H 2 S is expected to protect cancer cells from oxidative damage. Indeed, protein per-sulphidation is posited to confer a protection mechanism to prevent irreversible oxidation of protein cysteine residues.…”