Abstract
CD95 apoptosis resistance of tumor cells is often acquired through mutations in the death domain (DD) of one of the CD95 alleles. Furthermore, Type I cancer cells are resistant to induction of apoptosis by soluble CD95 ligand (CD95L), which does not induce efficient formation of the death-inducing signaling complex (DISC). Here, we report that tumor cells expressing a CD95 allele that lacks a functional DD, splenocytes from heterozygous Iprcg mice, which express one mutated CD95 allele, and Type I tumor cells stimulated with soluble CD95L can all die through CD95 when protein synthesis or nuclear factor kappa B is inhibited. This noncanonical form of CD95-mediated apoptosis is dependent on the enzymatic activity of procaspase-8 but does not involve fully processed active caspase-8 subunits. Our data suggest that it is possible to overcome the CD95 apoptosis resistance of many tumor cells that do not efficiently form a DISC through noncanonical activation of the caspase-8 proenzyme.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 25-37 |
| Number of pages | 13 |
| Journal | Cell Death and Differentiation |
| Volume | 12 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2005 |
Funding
We thank Drs P Krammer and H Walczak for providing us with anti-APO-1 and LzCD95L, respectively. We are grateful for Drs R DeMaria, A Payne and V Dixit for the Hut78 and H9 mutant cells and the crmA-expressing BJAB cells, respectively. The expression construct for human soluble CD95L was kindly provided by Dr S Nagata and the anti-mouse caspase-8 antibody by Dr A Strasser. This work was funded by the NIH Grant GM61712. A A-S was supported by the Cancer Biology Training Program 5T32CA09594 and BC. Barnhart by the DOD Breast Cancer Research Program DAMD17-03-1-0200.
Keywords
- Apoptosis
- CD95
- Caspase-8
- Death domain
- NF-kappaB
- Tumor cells
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
