title: 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.
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Panza
authors.forename: Paola
authors.initials: P
authors.lastname: De Cicco
authors.forename: Chiara
authors.initials: C
authors.lastname: Armogida
authors.forename: Giosuè
authors.initials: G
authors.lastname: Scognamiglio
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Gigantino
authors.forename: Gerardo
authors.initials: G
authors.lastname: Botti
authors.forename: Domenico
authors.initials: D
authors.lastname: Germano
authors.forename: Maria
authors.initials: M
authors.lastname: Napolitano
authors.forename: Andreas
authors.initials: A
authors.lastname: Papapetropoulos
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Bucci
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cirino
authors.forename: Angela
authors.initials: A
authors.lastname: Ianaro
mesh_terms: D000498:Allyl Compounds / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009362:Neoplasm Metastasis; D009506:Nevus / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D013440:Sulfides / Q000494:pharmacology; D013466:Sulfurtransferases / Q000235:genetics / Q000378:metabolism
chemical_list: D000498:Allyl Compounds; D016328:NF-kappa B; D013440:Sulfides; C042577:diallyl trisulfide; D013466:Sulfurtransferases; C021550:3-mercaptopyruvate sulphurtransferase; D003541:Cystathionine beta-Synthase; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide
keywords: apoptosis; cystathionine γ lyase; hydrogen sulfide; melanoma; nuclear factor-κB