Drug-induced Apoptosis in Lung Cancer Cells Is Not Mediated by the Fas/FasL (CD95/APO1) Signaling Pathway

• Published in: Clinical cancer research Vol. 6; no. 1; pp. 203 - 212
• Main Authors: FERREIRA, C. G, TOLIS, C, SPAN, S. W, PETERS, G. J, VAN LOPIK, T, KUMMER, A. J, PINEDO, H. M, GIACCONE, G
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-01-2000
• Subjects: Antineoplastic agents; Biological and medical sciences; General aspects; Medical sciences; Pharmacology. Drug treatments; Antineoplastic agent; Lung disease; Gemcitabine; Respiratory disease; Topotecan; Malignant tumor; In vitro; Bronchopulmonary; Cisplatin; Taxane derivatives; Established cell line; Paclitaxel; Bronchus disease; Fluorine Organic compounds; Pyrimidine nucleoside; Apoptosis; Platinum II Complexes
• ISSN: 1078-0432; 1557-3265

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.