TGF-beta1 inhibits Fas-mediated apoptosis by regulating surface Fas and cFLIPL expression in human leukaemia/lymphoma cells.

ABSTRACT

Transforming growth factor-beta1 (TGF-beta1) is a pleiotrophic cytokine that mediates differentiation, growth, and apoptosis. As a potent immunosuppressive agent, TGF-beta1 induces apoptosis in primary lymphocytes. However, it has been recognized that TGF-beta1 plays certain roles in development or progression of hematopoietic tumours via inhibition of Fas-mediated apoptotic cell death. Several studies have highlighted the mechanisms of TGF-beta1-induced Fas resistance and its contribution to aggressive tumour behavior. In this study, we have focused on the mechanisms by which TGF-beta1 protected leukaemia/lymphoma cells from Fas-mediated apoptosis. The presented study provides that TGF-beta1 inhibited Fas-mediated apoptosis of leukaemia/lymphoma cells in two distinct pathways. First, TGF-beta1 reduced expression of surface Fas receptors by blockade of trafficking cytoplasmic Fas to the surface, which allowed the leukaemia cells to resist Fas-mediated cell death. However, total Fas levels including both surface and cytoplasmic Fas were not altered, indicating that forced degradation of Fas or transcriptional regulation was not involved. Second, TGF-beta1 up-regulated Fas signaling pathway inhibitor cFLIPL to block the pro-caspase-8 cleavage and thus promoted survival of leukaemia/lymphoma cells. Our findings may partly explain why higher concentration of serum TGF-beta1 in cancer patient was related with poor prognosis.