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

Carlos G. Ferreira, Christos Tolis, Simone W. Span, Godefridus J. Peters, Thea Van Lopik, Alain J. Kummer, Herbert M. Pinedo, Giuseppe Giaccone

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)203-212
Number of pages10
JournalClinical Cancer Research
Volume6
Issue number1
StatePublished - Jan 2000
Externally publishedYes

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Lung Neoplasms
Apoptosis
Pharmaceutical Preparations
Cell Line
Monoclonal Antibodies
gemcitabine
Topotecan
Drug Therapy
Caspase 8
p53 Genes
Paclitaxel
Neutralizing Antibodies
Cisplatin
Up-Regulation
RNA
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Ferreira, C. G., Tolis, C., Span, S. W., Peters, G. J., Van Lopik, T., Kummer, A. J., ... Giaccone, G. (2000). Drug-induced apoptosis in lung cancer cells is not mediated by the Fas/FasL (CD95/APO1) signaling pathway. Clinical Cancer Research, 6(1), 203-212.

Drug-induced apoptosis in lung cancer cells is not mediated by the Fas/FasL (CD95/APO1) signaling pathway. / Ferreira, Carlos G.; Tolis, Christos; Span, Simone W.; Peters, Godefridus J.; Van Lopik, Thea; Kummer, Alain J.; Pinedo, Herbert M.; Giaccone, Giuseppe.

In: Clinical Cancer Research, Vol. 6, No. 1, 01.2000, p. 203-212.

Research output: Contribution to journalArticle

Ferreira, CG, Tolis, C, Span, SW, Peters, GJ, Van Lopik, T, Kummer, AJ, Pinedo, HM & Giaccone, G 2000, 'Drug-induced apoptosis in lung cancer cells is not mediated by the Fas/FasL (CD95/APO1) signaling pathway', Clinical Cancer Research, vol. 6, no. 1, pp. 203-212.
Ferreira CG, Tolis C, Span SW, Peters GJ, Van Lopik T, Kummer AJ et al. Drug-induced apoptosis in lung cancer cells is not mediated by the Fas/FasL (CD95/APO1) signaling pathway. Clinical Cancer Research. 2000 Jan;6(1):203-212.
Ferreira, Carlos G. ; Tolis, Christos ; Span, Simone W. ; Peters, Godefridus J. ; Van Lopik, Thea ; Kummer, Alain J. ; Pinedo, Herbert M. ; Giaccone, Giuseppe. / Drug-induced apoptosis in lung cancer cells is not mediated by the Fas/FasL (CD95/APO1) signaling pathway. In: Clinical Cancer Research. 2000 ; Vol. 6, No. 1. pp. 203-212.
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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.",
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