Role of the cystathionine γ lyase/hydrogen sulfide pathway in human melanoma progression

Abstract

In humans, two main metabolic enzymes synthesize hydrogen sulfide (H2 S): cystathionine γ lyase (CSE) and cystathionine β synthase (CBS). A third enzyme, 3-mercaptopyruvate sulfurtransferase (3-MST), synthesizes H2 S in the presence of the substrate 3-mercaptopyruvate (3-MP). The immunohistochemistry analysis performed on human melanoma samples demonstrated that CSE expression was highest in primary tumors, decreased in the metastatic lesions and was almost silent in non-lymph node metastases. The primary role played by CSE was confirmed by the finding that the overexpression of CSE induced spontaneous apoptosis of human melanoma cells. The same effect was achieved using different H2 S donors, the most active of which was diallyl trisulfide (DATS). The main pro-apoptotic mechanisms involved were suppression of nuclear factor-κB activity and inhibition of AKT and extracellular signal-regulated kinase pathways. A proof of concept was obtained in vivo using a murine melanoma model. In fact, either l-cysteine, the CSE substrate, or DATS inhibited tumor growth in mice. In conclusion, we have determined that the l-cysteine/CSE/H2 S pathway is involved in melanoma progression.

Hydrogen Sulfide and Cancer

“…Furthermore, four distinct human melanoma cell lines (A375, Sk-Mel-5, Sk-Mel-28 and PES 43), when compared in normal human epidermal melanocytes (NHEM) showed no increase in CBS expression. In contrast, another H 2 S-producing enzyme, CSE exhibited significantly higher expression in all of the nevi, melanoma samples and melanoma cell lines studied (Panza et al 2014). …”

“…Silencing of these enzymes did not affect melanoma cell proliferation (Panza et al 2014). These data indicate that in melanoma (as opposed to colon cancer and ovarian cancer), the expression of H 2 S-producing enzymes does not have an endogenous stimulatory role on cell proliferation.…”

Gasotransmitters in cancer: from pathophysiology to experimental therapy

“…CSE silencing suppressed tumour cell proliferation in vitro and in vivo in a colon cancer model 156 but CSE inhibition or CSE silencing failed to affect tumour cell proliferation in melanoma. 150 The functional role of changes of the levels of the various H 2 S-producing enzymes in most other types of cancer has not yet been explored.…”

Inhibition of hydrogen sulfide biosynthesis sensitizes lung adenocarcinoma to chemotherapeutic drugs by inhibiting mitochondrial DNA repair and suppressing cellular bioenergetics

“…The importance of the CBS/H 2 S in the promotion of cell proliferation and cellular bioenergetics has subsequently been confirmed in ovarian cancer13 and breast cancer14. H 2 S generated by overexpressed CSE, has been implicated in melanoma15. In addition a rapidly increasing body of literature implicates the endogenously generated H 2 S to vascular relaxation and angiogenesis, cell proliferation, mitochondrial function, and cell survival - all important factors in cancer biology16171819202122.…”