Role of the cystathionine γ lyase/hydrogen sulfide pathway in human melanoma progression |
| |
| Authors: | Elisabetta Panza Paola De Cicco Chiara Armogida Giosuè Scognamiglio Vincenzo Gigantino Gerardo Botti Domenico Germano Maria Napolitano Andreas Papapetropoulos Mariarosaria Bucci Giuseppe Cirino Angela Ianaro |
| |
| Affiliation: | 1. Department of Pharmacy, University of Naples Federico II, Naples, Italy;2. Unit of Pathology, Istituto Nazionale per lo Studio e la cura dei tumori Fondazione G. Pascale IRCCS, Naples, Italy;3. Oncology Unit, G. Rummo Hospital, Benevento, Italy;4. Department of Oncological Immunology, Istituto Nazionale per lo Studio e la cura dei tumori Fondazione Giovanni Pascale IRCCS, Naples, Italy;5. Faculty of Pharmacy, University of Athens, Athens, Greece |
| |
| Abstract: | In humans, two main metabolic enzymes synthesize hydrogen sulfide (H2S): cystathionine γ lyase (CSE) and cystathionine β synthase (CBS). A third enzyme, 3‐mercaptopyruvate sulfurtransferase (3‐MST), synthesizes H2S 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 H2S 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/H2S pathway is involved in melanoma progression. |
| |
| Keywords: | apoptosis cystathionine γ lyase hydrogen sulfide melanoma nuclear factor‐κ B |
|
|
