Hydrogen sulfide (H2S) is a gasotransmitter that exerts a multitude of functions in both physiologic and pathophysiologic processes. H2S-synthesizing enzymes are increased in a variety of human malignancies, including colon, prostate, breast, renal, urothelial, ovarian, oral squamous cell, and thyroid cancers. In cancer, H2S promotes tumor growth, cellular and mitochondrial bioenergetics, migration, invasion, angiogenesis, tumor blood flow, metastasis, epithelia–mesenchymal transition, DNA repair, protein sulfhydration, and chemotherapy resistance Additionally, in some malignancies, increased H2S-synthesizing enzyme expression correlates with a worse prognosis and a higher tumor stage. Here we review the role of H2S in cancer, with an emphasis on the molecular mechanisms by which H2S promotes cancer development, progression, dedifferentiation, and metastasis.
Background/Aim: Ethylmalonic encephalopathy 1 protein (ETHE1) plays an important role in sulfide catabolism and polysulfide formation. As sulfides and polysulfides have recently been identified as playing important roles in cancer, we hypothesized that ETHE1 expression would be increased in colon cancer. Materials and Methods: We used tissue microarray analysis to compare ETHE1 expression in benign colonic epithelium compared to colonic adenocarcinoma. In total, 26 benign colonic epithelial samples were compared to 122 cases of colonic adenocarcinomas. Results: Compared to benign colonic epithelium, ETHE1 expression was significantly increased (~two-fold) in colonic adenocarcinoma. Additionally, this expression increased with increasing colon cancer tumor grades. Conclusion: ETHE1 expression is increased in colon cancer compared to benign colonic epithelium. These data, combined with previous studies, suggest that ETHE1 may contribute to colon carcinogenesis by promoting tumor cell bioenergetics and polysulfide formation.Ethylmalonic encephalopathy 1 protein (ETHE1), also known as sulfur dioxygenase, is located on chromosome 19q13 and encodes a mettallo β-lactamase family enzyme containing a mononuclear iron center (1-4). Loss-of-function ETHE1 mutations are associated with ethylmalonic encephalopathy, a rare infantile autosomal recessive metabolic disorder affecting the brain, gastrointestinal tract, and peripheral vessels, characterized by psychomotor regression with generalized hypotonia, evolving into tetraparesis, dystonia, and subsequent global neurological failure and death in the first decade (3-5). Patients with ethylmalonic encephalopathy exhibit lactic acidemia, elevated urine ethylmalonic and methylsuccinic acids, and low skeletal muscle mitochondrial respiratory complex IV activity (3-5).ETHE1 functions in the mitochondrial matrix oxidizing sulfides to sulfate or sulfate esters, and taurine, through the sequential actions of sulfide: quinone oxidoreductase, ETHE1, and rhodanese (6). Specifically, ETHE1 detoxifies/oxidizes hydrogen sulfide (H2S) and glutathione polysulfides (glutathione-persulfide, -trisulfide, and -tetrasulfide), but not cysteine-or homocysteine-persulfides/polysulfides (6-8). Interestingly, ETHE1 also exhibits cysteine protein polysulfidation activities. ETHE1 persulfide dioxygenase and polysulfidation activities are dependent on Cys247 polysulfidation and replacement of the Cys247 with serine ablates both enzymatic activities (8). The enzymes that synthesize H2S, cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST), also function in polysulfide synthesis; suggesting that these enzymes and ETHE1 function together to regulate cellular polysulfide levels (8-10).Recently, one or more of the enzymes that synthesize H2S have been found to be increased in many different human malignancies, with one study of oral squamous cell carcinoma also showing significantly increased tumor H2S levels (11-13). Additionally, there is recent evide...
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