The potential role of hydrogen sulfide in cancer cell apoptosis

Abstract

For a long time, hydrogen sulfide (H₂S) has been considered a toxic compound, but recent studies have found that H₂S is the third gaseous signaling molecule which plays a vital role in physiological and pathological conditions. Currently, a large number of studies have shown that H₂S mediates apoptosis through multiple signaling pathways to participate in cancer occurrence and development, for example, PI3K/Akt/mTOR and MAPK signaling pathways. Therefore, the regulation of the production and metabolism of H₂S to mediate the apoptotic process of cancer cells may improve the effectiveness of cancer treatment. In this review, the role and mechanism of H₂S in cancer cell apoptosis in mammals are summarized.

Fig. 1. The production and metabolism of H₂S.

In mammals, H₂S is produced endogenously from cysteine, serine, homocysteine and other substrates primarily through the actions of three major enzymes. Non-enzymatic pathways: gut microbes as well as polysulfide-derived H₂S. Metabolism of H₂S: H₂S can be oxidized in the mitochondria or metabolized by methylation in the cytoplasm. H₂S is first oxidized by SQR in the mitochondria to form a persulfide. This persulfide is further oxidized by ETHE1 to produce SO₃²⁻, which is then converted to SO₄²⁻ and S₂O₃²⁻ by sulfite oxidase and rhodan oxidase and excreted in the urine or by respiration. H₂S can also be removed by binding to metalloproteins to form sulfheme. α-KG α-ketoglutaric acid, 3-MST 3-mercaptopyruvate sulfurtransferase, CAT cysteine aminotransferase, CBS cystathionine beta-synthase, CSE cystathionine gamma-lyase, CysS-SH cysteine persulfide, DAO D-amino acid oxidase, GSH glutathione, SAH S-adenosylhomocysteine, SAM S-adenosyl methionine, THF tetrahydrofolic acid.

Fig. 2. The mechanisms of H₂S function in the organism.

Promotion or inhibition of signaling pathways, post-translational modification of proteins, activation or shutdown of ion channels, and participation in mitochondrial metabolism. Akt protein kinase B, ERK extracellular signal-regulated kinase, JNK C-Jun N-terminal kinase, MAPK mitogen-activated protein kinase, NF-κB nuclear factor-kappa B, Nrf2 nuclear factor erythroid-2 related factor 2, PI3K phosphoinositide 3-kinase, STAT3 signal transducer and activator of transcription 3, TRPV1 transient receptor potential vanilloid 1.

Fig. 3. Several common H₂S donors.

DATS diallyl trisulfide, DADS diallyl disulfide, GYY4137 morpholin-4-ium 4-methoxyphenyl(morpholino) phosphinodithioate), SPRC S-propargyl-cysteine.

Fig. 4. The ways of DATS and DADS in the generation of H₂S.

DATS and DADS are two main active ingredients in garlic. DATS reacts rapidly with GSH to release H₂S via thiol−disulfide exchange followed by allyl perthiol reduction by GSH. DADS only releases a minute amount of H₂S via a sluggish reaction with GSH through an α-carbon nucleophilic substitution pathway. DATS diallyl trisulfide, DADS diallyl disulfide, GSH glutathione.

Fig. 5. H₂S regulates three pathways of apoptosis through multiple signaling pathways.

Cyt C cytochrome C, Fas fas cell surface death receptor, Fasl fas ligand, Smac second mitochondria-derived activator of caspases, JNK C-Jun N-terminal kinase, MAPK mitogen activated protein kinase, NF-κB nuclear factor-kappa B, PI3K phosphoinositide 3-kinase, Akt protein kinase B, ERs endoplasmic reticulum stress, ROS reactive oxygen species.