Drug-induced apoptosis in lung cancer cells is not mediated by the Fas/FasL (CD95/APO1) signaling pathway

Anticancer drugs exert at least part of their cytotoxic effect by triggerin g apoptosis, We previously identified chemotherapy-induced apoptosis in lun g cancer cells and suggested a I-ore for p53 alternative or complementary p athways in this process. Recently, a role for the Fas/FasL (CD95/Apo1) sign aling system in chemotherapy-induced apoptosis was proposed in some cell ty pes. Ln the present work, the involvement of the Fas/FasL system in drug-in duced apoptosis in lung cancer cells was investigated upon exposure to four cytotoxic drugs (cisplatin, gemcitabine, topotecan, and paclitaxel), We as sessed the expression of Fas and Fast and the function of the Fas pathway i n six lung cancer cell lines (H460, H322, GLC4, GLC4/ADR, H187, and N417), All lung cancer cell lines expressed Fas and Fast 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, aft er drug exposure, no significant Fast up-regulation was observed, whereas t he Fas expression was increased in the wild-type p53 cell line H460, but no t in the other lines, proved to be mutant p53 by direct gene sequencing. Mo reover, no correlation was observed in lung cancer cell lines between sensi tivity to drugs and to a Fas agonistic mAb, and preincubation of cells with either the Fas-antagonistic mAb CLB-CD95/2 or a Fast-neutralizing mAb did not protect from drug-induced apoptosis, Taken together, these observation strongly argue against a role of the Fas/FasL signaling pathway in drug-ind uced apoptosis in lung cancer cells. Interestingly, caspase-8 activation wa s observed upon drug exposure, independently from Fas/FasL signaling.