Emerging roles of hydrogen sulfide-metabolizing enzymes in cancer

Abstract

Gasotransmitters play crucial roles in regulating many physiological processes, including cell signaling, cellular proliferation, angiogenesis, mitochondrial function, antioxidant production, nervous system functions and immune responses. Hydrogen sulfide (H₂S) is the most recently identified gasotransmitter, which is characterized by its biphasic behavior. At low concentrations, H₂S promotes cellular bioenergetics, whereas at high concentrations, it can exert cytotoxic effects. Cystathionine β-synthetase (CBS), cystathionine-γ-lyase (CSE), 3-mercaptopyruvate sulfurtransferase (3-MST), and cysteinyl-tRNA synthetase 2 (CARS2) are pivotal players in H₂S biosynthesis in mammalian cells and tissues. The focus of this review is the regulation of the various pathways involved in H₂S metabolism in various forms of cancer. Key enzymes in this process include the sulfide oxidation unit (SOU), which includes sulfide:quinone oxidoreductase (SQOR), human ethylmalonic encephalopathy protein 1 (hETHE1), rhodanese, sulfite oxidase (SUOX/SO), and cytochrome c oxidase (CcO) enzymes. Furthermore, the potential role of H₂S methylation processes mediated by thiol S-methyltransferase (TMT) and thioether S-methyltransferase (TEMT) is outlined in cancer biology, with potential opportunities for targeting them for clinical translation. In order to understand the role of H₂S in oncogenesis and tumor progression, one must appreciate the intricate interplay between H₂S-synthesizing and H₂S-catabolizing enzymes.

Keywords: H2S; cysteine aminotransferase (CAT); ethylmalonic encephalopathy protein 1 (ETHE1); metabolism; sulfide quinone oxidoreductase (SQOR); sulfite oxidase (SUOX).

Figure 1.

Mechanistic role of H2S in breast cancer (BC) cells. Implication of H₂S in BC oncogenesis by controlling oxidative stress, angiogenesis, migration, apoptosis, and immunogenicity. 4-HNE: 4-Hydroxynonenal; Akt: Protein kinase B; ERK1/2: extracellular signal-regulated kinase 2; FAK: Focal adhesion kinase; GSH: Glutathione; HIFI-a: hypoxia-inducible factor-1 alpha; IFN-y: interferon gamma; JAK: Janus kinase; MDA: Malondialdehyde; MICA: MHC class I polypeptide – related sequence A; MMP2/9: matrix metalloproteinase-2/9; mTOR: mammalian target of rapamycin; PI3K: phosphoinositide 3-kinase; SERPINF1: serpin F1; SIRT1: Sirtuin-1; STAT3: Signal transducer and activator of transcription 3; TGF-β1: transforming growth factor beta-1; ULBP2: UL16-binding protein 2; VEGF: vascular endothelial growth factor.

Figure 2.

H₂S metabolic pathways. (A). Anabolic pathways of H₂S in the cytoplasm and mitochondrial matrix. (B). Enzymatic and nonenzymatic catabolic pathways of H₂S either through oxidation or methylation, where oxidation occurs in the mitochondria enzymatically or in the blood nonenzymatically. CBS: cystathionine β synthase; CSE: cystathionine γ-lyase; 3MST: 3-mercaptopyruvate sulfurtransferase; CAT: cysteine aminotransferase; SQOR: sulfide quinone oxidoreductase; hETHE1: human ethylmalonic encephalopathy protein 1; Rhod: rhodanese; SUOX: sulfite oxidase; TR: thiosulfate reductase; SR: sulfur transferase; III: complex III; IV: complex IV; TMT: thiol S-methyltransferase; Hb: hemoglobin; MetHb: methemoglobin.