Molecular Functions of Hydrogen Sulfide in Cancer

Abstract

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.

Bad Smells and Broken DNA: A Tale of Sulfur-Nucleic Acid Cooperation

“…Support for this comes from analyses demonstrating that reactive oxygen and reactive sulfur species detoxifying mechanisms have been present since the origin of life, some four billion years ago, and have continued to the present in the biochemistry of the Archaea, Bacteria, and Eukarya [50][51][52][53][54][55][56]. Since genomic stability maintenance is an ancient and absolute requirement for life, and H 2 S biochemistry is similarly ancient and ubiquitous, it is very likely that H 2 S functioned in the earliest biochemical pathways including in those regulating genomic stability [1][2][3][11][12][13]17,[52][53][54][55][56][57][58].…”

“…Increased H 2 S synthesis and CBS, CSE, and/or 3-MST expression promote cancer progression in several human malignancies, and H 2 S synthesis inhibitors have been proposed as a cancer treatment [5,11,12,17,69,92,93]. In addition, ATR inhibitors are showing promise in phase I and II clinical trials for lung, ovarian, cervical, urothelial, and advanced sold tumors [93].…”

“…Moreover, all three proteins regulate autophagy and mitochondrial function and viability [97][98][99][100]. These observations, combined with the ancient and parallel origins of H 2 S biochemistry and DNA repair, and with H 2 S now linked to mitochondrial and nuclear DNA repair, suggest that ATM and DNA-PK may also regulate aspects of H 2 S metabolism [1][2][3][11][12][13]17,[52][53][54][55][56][57][58]. Although only hypotheses, these ideas could be easily tested.…”

“…Hydrogen sulfide (H 2 S) is a gasotransmitter that, along with nitric oxide and carbon monoxide, functions in a vast number of different physiologic and pathophysiologic processes [8,9]. Specifically, H 2 S has many physiologic regulatory roles, including in the renal, cardiovascular, central nervous, and digestive systems, and is also dysregulated in many different pathologic processes including cancer, cardiovascular diseases, and neurodegeneration [10][11][12][13][14][15][16][17]. Recently, H 2 S has been found to regulate mitochondrial and nuclear DNA stability and repair [11][12][13].…”

Hydrogen Sulfide Biology and Its Role in Cancer

“…H 2 S has become widely accepted as a critical signaling molecule in cancer biology due to its unique chemistry, molecular reactivity mechanisms, capacity to change proteins, and active participation in numerous redox processes with metal. H 2 S has been implicated in a variety of physiological processes linked to the cell cycle and tumor progression, including angiogenesis, tumor growth, cellular and mitochondrial biogenesis, tumor blood flow, migration and invasion, metastasis, protein sulfhydration, epithelial-mesenchymal transition, DNA repair, and chemotherapy resistance [ 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. There are numerous publications describing the potential roles of H 2 S in cancer [ 32 ], such as Cao et al [ 32 ] and Shackelford et al [ 27 ].…”