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  • Title: Activation of the Fas pathway independently of Fas ligand during apoptosis induced by camptothecin in p53 mutant human colon carcinoma cells.
    Author: Shao RG, Cao CX, Nieves-Neira W, Dimanche-Boitrel MT, Solary E, Pommier Y.
    Journal: Oncogene; 2001 Apr 05; 20(15):1852-9. PubMed ID: 11313933.
    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.
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