TRANSCRIPTION FACTORS AS TARGETS OF NEW MOLECULES WITH POTENTIAL ANTI-CANCER ACTIVITY

Abstract

Melanoma is the deadliest form of skin cancer and it is rising in incidence. Although in the past 3 years have been made notable advances in the understanding the molecular pathogenesis of melanoma and its treatment, melanoma therapy is still a challenge. Therefore, it is critical to identify other important potential targets in melanoma development and progression that are amenable to pharmacological inhibition. In the last few years, numerous physiological and pathophysiological effects have been proposed for the gasotransmitter hydrogen sulphide, even its role in cancer molecular mechanisms is still unclear. Recently, it has been shown that CSE enzyme is expressed in melanoma cell lines and that CBS enzyme plays a key role in colon and ovarian cancer. Starting from these evidence, the aim of my PhD project was to investigate the role of the metabolic H2S pathway in human melanoma. Our study have demonstrate that H2S inhibited melanoma cell proliferation inducing apoptosis and cell cycle arrest in G0/G1-phase.The main pro-apoptotic mechanisms involved were suppression of nuclear factor-kB activity and inhibition of the AKT and ERK pathways.The anti-proliferative role of H2S was also confirmed by the finding that the overexpression of CSE induced spontaneous apoptosis of human melanoma cells. A proof of concept was obtained in vivo using both a murine model of cutaneus melanoma and a murine model of metastatic melanoma. In fact, either L-cysteine, the CSE substrate, or DATS inhibited tumor growth and the development of lung metastases in mice. Finally, 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 metastase whereas CBS and 3-MST do not appear to play an important role in human melanoma. These data support our hypothesis that CSE derived hydrogen sulfide plays a major role in melanoma.In conclusion, we have determined that the L-cysteine/CSE/H2S pathway is involved in melanoma progression.