IBYME   02675
INSTITUTO DE BIOLOGIA Y MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
THE MACROLIDE FK506 REDUCES MELANOMA CELL PROLIFERATION VIA NF-KB INACTIVATION
Autor/es:
ZGAJNAR NR, DE LEO SA, ERLEJMAN AG, GALIGNIANA MD
Lugar:
Melbourne
Reunión:
Congreso; International Congress of Immunology; 2016
Resumen:
FK506-binding protein 51 (FKBP51) is a soluble immunophilin able to bind the immunosuppressant macrolide FK506. Recently, we demonstrated that FKBP51 forms complexes with NF-kB, and shows antiapoptotic action in tumor cells. FKBP51 is hardly detectable in normal melanocytes, and highly induced in melanoma cells favoring tumor aggressiveness and therapy resistance. NF-kB has been related to cancer since its discovery. Specific mutations strongly activate NF-kB in lymphoid malignancies. Nonetheless, no mutations have been identified to date for solid tumors, where NF-kB activation appears to be related to inflammation and/or the formation of proinflammatory microenvironments during malignant progression by up-regulation of tumor-promoting cytokines such as IL-6 or TNF-alpha. We hypothesized that FKBP51 could be involved in an FK506-dependent manner in the inflammatory response mechanism. Here we report that FKBP51 is overexpressed in several tumor cell lines and translocates to the nucleus in the presence of TNF-alpha. FKBP51 overexpression prevents NF-kB nuclear translocation and its biological activity. When B16 melanoma cells, a standard experimental model for human melanoma, were stimulated with PMA, both NF-kB nuclear relocalization and endogenous production of IL-6 were favored. These expected effects were fully prevented by co-incubation with FK506 or PDTC (pyrrolidine-carbodithioate), a known NF-kB inhibitor. Interestingly, controls with FK506 alone already showed lower basal nuclear accumulation of NF-kB and IL-6 secretion than untreated cells. FK506 also showed similar results in co-cultures of B16 cells with mouse spleen lymphocytes. It is postulated that FK506 reduces melanoma cell proliferation by inhibition of the NF-kB signalling cascade via FKBP51.