The role of Fas and FasL as mediators of anticancer chemotherapy

Fas Ligand (FasL) is a member of the TNF superfamily that induces apoptosis in susceptible cells upon cross-linking of its own receptor, Fas (Apo-1/CD95). FasL-induced apoptosis contributes to immune homeostasis and cell-mediated cytotoxicity. Several groups have suggested that it also participates in the mechanism of action of DNA-damaging anticancer drugs. However, others have disputed this hypothesis, based largely on the inability of exogenously added anti-Fas/FasL reagents to attenuate drug-induced apoptosis in their studies. In this minireview, we discuss the most recent evidence for and against the involvement of FasL/Fas in the sensitivity and resistance to chemotherapy in a variety of models. In our own model of Ewing's sarcoma (ES), we have extensively investigated the involvement of the FasL/Fas pathway in doxorubicin (Dox)-induced apoptosis. We have generated clones of the Fas-sensitive, Dox-sensitive ES cell line SK-N-MC that were either Fas-resistant or FasL-deficient, and found that they were significantly resistant to Dox. Cleavage of FasL by MMP-7 (matrilysin) protected the parental SK-N-MC cells from Dox, whereas inhibition of MMP-7 activity increased their sensitivity. Transfection of a construct encoding soluble (decoy) Fas protected SK-N-MC cells from Dox. However, incubation with anti-Fas or anti-FasL neutralizing antibodies or exogenous addition of pre-synthesized recombinant soluble Fas decoy protein had no protective effect. This raises the possibility that the proposed Fas/FasL suicidal interaction may take place in an intracellular compartment and thus is not accessible to exogenously added reagents. Therefore, commercially available Fas/FasL neutralizing reagents may not be a reliable indicator of the involvement of the Fas pathway in anticancer-drug-induced apoptosis and experiments using these agents should be carefully re-evaluated. The combined use of MMP inhibitors with conventional, cytotoxic chemotherapy may hold therapeutic benefit.