Matrix metalloproteinase-7-mediated cleavage of Fas ligand protects tumor cells from chemotherapeutic drug cytotoxicity

Recent evidence suggests that one mechanism whereby cytotoxic drugs, such a s doxorubicin, kill tumors is the induction or up-regulation of Fas ligand (FasL) expression on the tumor cell surface. The ensuing engagement of Fas by FasL on adjacent cells leads to apoptosis, However, despite cytotoxic dr ug-induced Fast expression, Fas-sensitive tumors frequently resist chemothe rapy, suggesting that they may possess a mechanism that prevents or inactiv ates Fas-FasL interactions. In the present work, we addressed the involveme nt of the FasL/Fas signaling pathway in doxorubicin-indureed apoptosis and the ability of matrix metalloproteinases (MMPs) to proteolytically cleave F ast in tumor cells. Doxorubicin-induced apoptosis was inhibited by expressi on of soluble Fas or incubation of the tumor cells with MMP-7 but not with MMP-2 or MMP-9, Resistance to doxorubicin was also induced by expression in the tumor cells of constitutively active MMP-7 but not of a catalytically inactive mutant. Conversely, inhibition of MMP-7 expression in tumor cells by transfection of MMP-7 cDNA in antisense orientation resulted in sensitiz ation to doxorubicin, MMP-7 efficiently cleaved recombinant Fast ill vitro and reduced cell surface FasL expression. Our observations provide evidence that one mechanism whereby MMP-7 may promote tumor survival and resistance to doxorubicin is by cleaving Fast and reducing its effectiveness in trigg ering Fas-mediated apoptosis.