Activation of the Fas pathway independently of Fas ligand during apoptosis induced by camptothecin in p53 mutant human colon carcinoma cells

Rong Guang Shao, Chun Xia Cao, Wilberto Nieves-Neira, Marie Thérèse Dimanche-Boitrel, Eric Solary, Yves Pommier

Research output: Contribution to journalArticle

80 Scopus citations

Abstract

The present study explored the role of the cell surface receptor Fas (CD95/APO-1) in apoptosis induced by camptothecin (CPT) in the HT29 colon carcinoma cell line. CPT-induced apoptosis was associated with high molecular weight DNA fragmentation as measured by filter elution. This fragmentation was inhibited by the caspase inhibitor, z-VAD-fmk and by cycloheximide, which also prevented proteolytic activation of caspase-3 and poly(ADP-ribose)polymerase cleavage. Under such conditions, Fas, Fas ligand, Bax, and p21 expression were increased and Fas recruited the FADD adaptor. Fas expression increase was blocked by cycloheximide but not by z-VAD-fmk, consistent with caspase activation downstream from Fas. Treatment of HT29 cells with FasL or with the CH-11 agonistic anti-Fas antibody potentiated the apoptotic response of cells treated with CPT. The anti-Fas blocking antibody ZB4 and the Fas-ligand inhibitor failed to protect HT29 cells from CPT-induced apoptosis. Such a protection was obtained by transient expression of constructs encoding a dominant-negative mutant of FADD, FADD in an antisense orientation and E8 or MC159 viral proteins that inhibit Fas-induced apoptosis at the level of FADD and procaspase-8, respectively. Together, these data show that topoisomerase I-mediated DNA damage-induced apoptosis involves activation of the Fas pathway without detectable Fas-ligand requirement in CPT-treated cells.

Original languageEnglish (US)
Pages (from-to)1852-1859
Number of pages8
JournalOncogene
Volume20
Issue number15
DOIs
StatePublished - Apr 5 2001

Keywords

  • Bax
  • Caspase
  • FADD
  • Nuclease
  • Programmed cell death
  • z-VAD

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Shao, R. G., Cao, C. X., Nieves-Neira, W., Dimanche-Boitrel, M. T., Solary, E., & Pommier, Y. (2001). Activation of the Fas pathway independently of Fas ligand during apoptosis induced by camptothecin in p53 mutant human colon carcinoma cells. Oncogene, 20(15), 1852-1859. https://doi.org/10.1038/sj.onc.1204264