Studio del ruolo della proteina anti-apoptotica BAG3 nel melanoma umano

Abstract

BAG3 protein, a member of BAG family of co-chaperones, has a pro-survival role in several tumor types. BAG3 anti-apoptotic properties rely on its characteristic to bind several intracellular partners, thereby modulating crucial events such as apoptosis, differentiation, cell motility and autophagy. In human melanomas, BAG3 positivity is correlated with the aggressiveness of the tumor cells and can sustain IKK-γ levels, allowing a sustained activation of NF-B. Furthermore, BAG3 is able to modulate BRAFV600E levels and activity in thyroid carcinomas. BRAFV600E mutation is the most frequent detected in malignant melanomas and is targeted by Vemurafenib, a molecule used for the treatment of advanced melanoma. However a subset of patients resulted not sensitive or acquired resistance to this molecule. Here we confirmed that BAG3 expression is significantly enhanced in metastasis in respect to primary tumors, than we demonstrated that BAG3 protein expression was significantly enhanced in metastasis of patients carring BRAFV600E mutation. Furthermore we found a significant correlation between BAG3 positivity and patients’ overall survival (OS), disease-specific survival (DSS) and disease-free survival (DFS) from surgery in patients with melanoma metastatic lymph nodes. Moreover here we show that BAG3 down-modulation interferes with BRAF levels in melanoma cells and sensitizes them to Vemurafenib treatment. Furthermore, in an in vitro model of acquired resistance to Vemurafenib, we demonstrated that the down-modulation of BAG3 protein can resensitize this cells to BRAFV600E specific inhibition interfering with BRAF pathway, causing reduction of ERK and its targets phosphorylation. Further studies will be focused in demonstrating our hypothesis that the molecular interactions between BAG3 and mutated BRAF can represent a target for novel multi-drugs treatment design and that BAG3 expression could contribute to prognosis and patient stratification for specific therapeutic approaches. [edited by Author]