Inhibition of metalloproteinase cleavage enhances the cytotoxicity of Fas ligand.
The Fas ligand (FasL)/Fas receptor (CD95) pathway is an important mediator of apoptosis in the immune system and can also mediate cancer cell death. Soluble FasL (sFasL), shed from the membrane-bound form of the molecule by a putative metalloproteinase (MP), may function to locally regulate the activity of membrane-bound FasL. Using a replication-defective recombinant adenovirus-expressing FasL (RAdFasL), we identified a variable ability of different carcinoma cells to respond to FasL-induced cytotoxicity and to shed sFasL. Blockade of FasL cleavage with an MP inhibitor significantly enhanced RAdFasL-induced apoptosis suggesting that sFasL may antagonize the effect of membrane-bound FasL. In support of this concept, a recombinant adenovirus expressing a noncleavable form of FasL (RAdD4) was found to be a potent inducer of apoptosis even at very low virus doses. Our results highlight the therapeutic potential of noncleavable FasL as an antitumor agent and emphasize the important role of MP via the production of sFasL in regulating the response of the Fas pathway. Moreover, these findings have general implications for the therapeutic exploitation of TNF family ligands and for the possible impact of MP-based therapies on the normal physiology of Fas/TNF pathways.
Knox
Pauline G
PG
Cancer Research United Kingdom Institute for Cancer Studies, University of Birmingham Medical School, Edgbaston, United Kingdom.
Milner
Anne E
AE
Green
Nicky K
NK
Eliopoulos
Aristides G
AG
Young
Lawrence S
LS
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000276:Adjuvants, Immunologic / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000633:toxicity; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D053222:Fas Ligand Protein; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000276:immunology / Q000633:toxicity; D006801:Humans; D006868:Hydrolysis; D008024:Ligands; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000633:toxicity*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D011995:Recombination, Genetic; D012995:Solubility; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D019014:fas Receptor / Q000378:metabolism*
D000276:Adjuvants, Immunologic; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008024:Ligands; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein