CD95 ligand induces motility and invasiveness of apoptosis-resistant tumor cells.
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 TNFalpha or TRAIL. Three signaling pathways resulting in activation of NF-kappaB, 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.
Barnhart
Bryan C
BC
The Ben May Institute for Cancer Research, Committee on Immunology, The University of Chicago, Chicago, IL 60637-5420, USA.
Legembre
Patrick
P
Pietras
Eric
E
Bubici
Concetta
C
Franzoso
Guido
G
Peter
Marcus E
ME
D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D053222:Fas Ligand Protein; D006801:Humans; D020935:MAP Kinase Signaling System; D008562:Membrane Glycoproteins / Q000378:metabolism* / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D014568:Urokinase-Type Plasminogen Activator; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases