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 tumorigenesi s. Fas, a member of the tumor necrosis factor receptor superfamily, is a tr ansmembrane protein that can transduce cell death signals via a proteolytic cascade upon crosslinking or ligand binding. Fas has been implicated in th e cell turnover of normal stratified squamous epithelia. To determine if al tered Fas mediated cell death pathways participate in epithelial tumorigene sis, we examined squamous cell carcinoma (SCC) lines for sensitivity to Fns ligand (FasL) or an agonistic anti-Fas antibody. All cell lines examined w ere resistant to Fast mediated cell death. The carcinoma cell line SCC71 wa s 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 Fast and anti-Fas antibody r ecruited downstream effector molecules to the Fas cytoplasmic domain in bot h 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 e xpression of the anti-apoptotic protein bcl2. We concluded that Fas differe ntially mediates apoptosis in SCC lines by activation of caspase 3 family m embers but independent of bcl2 expression.