Hydrogen Sulfide and Cancer

Abstract

Recent studies revealed increased expression of various hydrogen sulfide (H2S) producing enzymes in cancer cells of various tissue types, and new roles of H2S in the pathophysiology of cancer have emerged. This is particularly evident in cancers of the colon and ovaries, where the malignant cells both overexpress cystathionine-β-synthase (CBS) and produce increased amounts of H2S, which enhances tumor growth and spread by (a) stimulating cellular bioenergetics, (b) activating proliferative, migratory, and invasive signaling pathways, and (c) enhancing tumor angiogenesis. Importantly, in preclinical models of these cancers, either pharmacological inhibition or genetic silencing of CBS was shown to be sufficient to suppress cancer cell bioenergetics in vitro, inhibit tumor growth and metastasis in vivo, and enhance the antitumor efficacy of front-line chemotherapeutic agents, providing a strong rationale for the development of CBS-targeted inhibitors as anticancer therapies. However, the observation that inhibition of H2S biosynthesis exerts anticancer effects is contradicted by other studies showing that increasing H2S with exogenous donors also exert antitumor actions. Herein, we present a brief review of the scientific literature documenting the function of H2S, H2S donors, and transsulfuration enzymes in cancers from various tissue types, and propose that the paradoxical actions of H2S can be resolved by considering the bell-shaped pharmacology of H2S, whereby lower (endogenous) H2S production tend to promote, while higher (generated from exogenously added H2S donors) tend to inhibit cancer cell proliferation. Finally, we suggest areas for future investigations to expand our knowledge of this nascent field.

The dichotomous role of H2S in cancer cell biology? Déjà vu all over again

“…CSE has also been reported to have a high expression in colon, melanoma, lung, and prostate cancers [104–106]; while MST is reported to be high in glioma and melanoma [34, 104, 107]. …”

Upregulation of Cystathionine-β-Synthase in Colonic Epithelia Reprograms Metabolism and Promotes Carcinogenesis

“…Cysteine is used for the biosynthesis of proteins, glutathione, and the gaseous transmitter hydrogen sulfide (H 2 S), which is produced by both CBS and CSE (2). In established colorectal cancers and cancer-derived cell lines, CBS-dependent production of H 2 S, and not CSE produced H 2 S, has been shown to regulate cellular bioenergetics in a context-specific and concentration-dependent manner (3,4). The CBS-H 2 S signaling axis promotes colorectal cancer growth and metastasis through cancer cell autonomous regulation of cellular proliferation, migration, and bioenergetics, as well as paracrine regulation of tumor angiogenesis (1).…”

The chemical biology of the persulfide (RSSH)/perthiyl (RSS·) redox couple and possible role in biological redox signaling

“…For example, H 2 S has been reported to be involved in the etiology of atherosclerosis [4] and cancer [5], regulate transcription via NRF2/KEAP1 [6] or NF-κB[7], control vascular tone [8], inhibit phosphodiesterase activity [9], protect against neurodegenerative diseases [10] and protect from ischemia-reperfusion toxicity [11], just to name a few. Current interest in the chemical biology of H 2 S has been motivated primarily by the reports of its biological activity and potential therapeutic utility.…”