TGF-beta1 inhibits Fas-mediated apoptosis by regulating surface Fas and cFLIPL expression in human leukaemia/lymphoma cells.
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.
Jung
Young-Joo
YJ
Department of Pathology, College of Medicine, Kyung Hee University, Seoul 130-701, Korea.
Kim
Jee-Youn
JY
Park
Jae-Hoon
JH
D017209:Apoptosis / Q000502:physiology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007938:Leukemia / Q000378:metabolism*; D008223:Lymphoma / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D019014:fas Receptor / Q000378:metabolism*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D019014:fas Receptor