Non-apoptotic Fas signaling regulates invasiveness of glioma cells and modulates MMP-2 activity via NFkappaB-TIMP-2 pathway.
Fas (CD95/APO-1) is a cell surface "death receptor" that mediates apoptosis upon engagement by its ligand, FasL. Paradoxically, Fas/FasL can also promote cell invasion among non-apoptotic cells; here, we show that Fas/FasL signaling can promote tumor invasion when apoptosis is compromised. We have developed a recombinant FasL Interfering Protein (FIP) to interfere with Fas signaling in C6 glioma cells expressing both Fas receptor and its ligand. FIP administration did not affect cell viability but impaired cell motility and invasiveness of glioma cells. Blockade of Fas signaling reduced MMP-2 activity in glioma cells, that was associated with down-regulation of MAPK signaling, and AP-1 and NFkappaB-driven transcription. FIP treatment did not affect mmp-2 and mt1-mmp expression but significantly attenuated timp-2 expression and TIMP-2 amount in the culture medium. Studies with pharmacological inhibitors of JNK/c-Jun (SP600125) and NFkappaB (BAY11-7082) signaling pathways demonstrated that timp-2 expression is regulated by NFkappaB transcription factor. Our findings show that non-apoptotic Fas signaling activated in the autocrine manner or through microenvironment derived factors can regulate invasiveness of glioma cells via modulation of MMP-2 activation, likely by controlling TIMP-2 expression.
Dept. Cell Biology, The Nencki Institute of Experimental Biology, Warsaw, Poland.
Pawel
P
Wisniewski
Aleksandra
A
Ellert-Miklaszewska
Aneta
A
Kwiatkowska
Bozena
B
Kaminska
D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D051381:Rats; D015398:Signal Transduction; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism*; D051720:Upstream Stimulatory Factors / Q000494:pharmacology; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
D053222:Fas Ligand Protein; D016328:NF-kappa B; C497184:USF2 protein, human; D051720:Upstream Stimulatory Factors; D019014:fas Receptor; D019716:Tissue Inhibitor of Metalloproteinase-2; D048031:JNK Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2