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J. Exp. Med.,
Volume 188, Number 5, September 7, 1998 919-930
By
From the Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology and
University of Ghent, B-9000 Ghent, Belgium
Murine L929 fibrosarcoma cells were transfected with the human Fas (APO-1/CD95) receptor,
and the role of various caspases in Fas-mediated cell death was assessed. Proteolytic activation of procaspase-3 and -7 was shown by Western analysis. Acetyl-Tyr-Val-Ala-Asp-chloromethylketone and benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethylketone, tetrapeptide inhibitors of caspase-1- and caspase-3-like proteases, respectively, failed to block
Fas-induced apoptosis. Unexpectedly, the broad-spectrum caspase inhibitors benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone and benzyloxycarbonyl-Asp(OMe)-fluoromethylketone rendered the cells even more sensitive to Fas-mediated cell death, as measured after 18 h
incubation. However, when the process was followed microscopically, it became clear that
anti-Fas-induced apoptosis of Fas-transfected L929 cells was blocked during the first 3 h, and
subsequently the cells died by necrosis. As in tumor necrosis factor (TNF)-induced necrosis,
Fas treatment led to accumulation of reactive oxygen radicals, and Fas-mediated necrosis was
inhibited by the oxygen radical scavenger butylated hydroxyanisole. However, in contrast to
TNF, anti-Fas did not activate the nuclear factor 
B under these necrotic conditions. These results demonstrate the existence of two different pathways originating from the Fas receptor, one
rapidly leading to apoptosis, and, if this apoptotic pathway is blocked by caspase inhibitors, a
second directing the cells to necrosis and involving oxygen radical production.
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