title: Drug-induced apoptosis in lung cnacer cells is not mediated by the Fas/FasL (CD95/APO1) signaling pathway.
abstract: Anticancer drugs exert at least part of their cytotoxic effect by triggering apoptosis. We previously identified chemotherapy-induced apoptosis in lung cancer cells and suggested a role for p53 alternative or complementary pathways in this process. Recently, a role for the Fas/FasL (CD95/Apo1) signaling system in chemotherapy-induced apoptosis was proposed in some cell types. In the present work, the involvement of the Fas/FasL system in drug-induced apoptosis in lung cancer cells was investigated upon exposure to four cytotoxic drugs (cisplatin, gemcitabine, topotecan, and paclitaxel). We assessed the expression of Fas and FasL and the function of the Fas pathway in six lung cancer cell lines (H460, H322, GLC4, GLC4/ADR, H187, and N417). All lung cancer cell lines expressed Fas and FasL at RNA and protein levels, and apoptosis could be induced in four of six cell lines upon exposure to the Fas agonistic monoclonal antibody (mAb) CLB-CD95/15. Nevertheless, after drug exposure, no significant FasL up-regulation was observed, whereas the Fas expression was increased in the wild-type p53 cell line H460, but not in the other lines, proved to be mutant p53 by direct gene sequencing. Moreover, no correlation was observed in lung cancer cell lines between sensitivity to drugs and to a Fas agonistic mAb, and preincubation of cells with either the Fas-antagonistic mAb CLB-CD95/2 or a FasL-neutralizing mAb did not protect from drug-induced apoptosis. Taken together, these observations strongly argue against a role of the Fas/FasL signaling pathway in drug-induced apoptosis in lung cancer cells. Interestingly, caspase-8 activation was observed upon drug exposure, independently from Fas/FasL signaling.
authors.affiliation: Division of Medical Oncology, University Hospital Vrije Universiteit Amsterdam, The Netherlands.
authors.forename: C G
authors.initials: CG
authors.lastname: Ferreira
authors.forename: C
authors.initials: C
authors.lastname: Tolis
authors.forename: S W
authors.initials: SW
authors.lastname: Span
authors.forename: G J
authors.initials: GJ
authors.lastname: Peters
authors.forename: T
authors.initials: T
authors.lastname: van Lopik
authors.forename: A J
authors.initials: AJ
authors.lastname: Kummer
authors.forename: H M
authors.initials: HM
authors.lastname: Pinedo
authors.forename: G
authors.initials: G
authors.lastname: Giaccone
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002289:Carcinoma, Non-Small-Cell Lung; D018288:Carcinoma, Small Cell; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002945:Cisplatin / Q000633:toxicity; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000633:toxicity; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D016158:Genes, p53; D006801:Humans; D008175:Lung Neoplasms; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D017239:Paclitaxel / Q000633:toxicity; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D019772:Topotecan / Q000633:toxicity; D014162:Transfection; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000235:genetics / Q000502:physiology*; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D019014:fas Receptor; D003841:Deoxycytidine; D019772:Topotecan; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D017239:Paclitaxel; D002945:Cisplatin; D000093542:Gemcitabine