Article
- The EMBO Journal (2004) 23, 3175 - 3185
- doi:10.1038/sj.emboj.7600325
Published online: 22 July 2004
Subject Categories:
CD95 ligand induces motility and invasiveness of apoptosis-resistant tumor cells
Bryan C Barnharta, Patrick Legembrea, Eric Pietras, Concetta Bubici, Guido Franzoso and Marcus E Peter
- The Ben May Institute for Cancer Research, Committees on Immunology and Cancer Biology, The University of Chicago, Chicago, IL, USA
Correspondence to:
Marcus E Peter, The Ben May Cancer Institute, University of Chicago, 924 East 57th Street, R112, Chicago, IL 60637-5420, USA. Tel.: +1 773 702 4728; Fax: +1 773 702 3701; E-mail: mpeter@uchicago.edu
aThese authors contributed equally to this work
Received 17 February 2004; Accepted 21 June 2004
Abstract
The apoptosis-inducing death receptor CD95 (APO-1/Fas) controls the homeostasis of many tissues. Despite its apoptotic potential, most human tumors are refractory to the cytotoxic effects of CD95 ligand. We now show that CD95 stimulation of multiple apoptosis-resistant tumor cells by CD95 ligand induces increased motility and invasiveness, a response much less efficiently triggered by TNF
or TRAIL. Three signaling pathways resulting in activation of NF-
B, Erk1/2 and caspase-8 were found to be important to this novel activity of CD95. Gene chip analyses of a CD95-stimulated tumor cell line identified a number of potential survival genes and genes that are known to regulate increased motility and invasiveness of tumor cells to be induced. Among these genes, urokinase plasminogen activator was found to be required for the CD95 ligand-induced motility and invasiveness. Our data suggest that CD95L, which is found elevated in many human cancer patients, has tumorigenic activities on human cancer cells. This could become highly relevant during chemotherapy, which can cause upregulation of CD95 ligand by both tumor and nontumor cells.
Keywords:
- apoptosis,
- CD95,
- gene chip,
- invasiveness,
- NF-B
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