Anti-Fas antibody differentially regulates apoptosis in Fas ligand resistant carcinoma lines via the caspase 3 family of cell death proteases but independently of bcl2 expression.
Deregulation of cell death pathways is an important feature of tumorigenesis. Fas, a member of the tumor necrosis factor receptor superfamily, is a transmembrane protein that can transduce cell death signals via a proteolytic cascade upon crosslinking or ligand binding. Fas has been implicated in the cell turnover of normal stratified squamous epithelia. To determine if altered Fas mediated cell death pathways participate in epithelial tumorigenesis, we examined squamous cell carcinoma (SCC) lines for sensitivity to Fas ligand (FasL) or an agonistic anti-Fas antibody. All cell lines examined were resistant to FasL mediated cell death. The carcinoma cell line SCC71 was also highly resistant to anti-Fas antibody. Another line, SCC9, underwent rapid cell death with characteristic features of apoptosis after exposure to anti-Fas antibody. However, binding of both FasL and anti-Fas antibody recruited downstream effector molecules to the Fas cytoplasmic domain in both SCC9 and SCC71 cells. Inhibition of the caspase 3- but not the ICE family of cell death proteases blocked apoptosis in SCC9 cells independently of expression of the anti-apoptotic protein bcl2. We concluded that Fas differentially mediates apoptosis in SCC lines by activation of caspase 3 family members but independent of bcl2 expression.
Crowe
D L
DL
Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles 90033, USA.
Boardman
M L
ML
Fong
K S
KS
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000503:physiopathology; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D053938:DNA Fragmentation; D053222:Fas Ligand Protein; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; D061945:Caspase Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases