Camptothecin induces the transit of FasL trimers to the cell surface in apoptotic HEp-2 cells

Abstract

Fas ligand (L) is a membrane protein from the tumor necrosis factor (TNF) family. It induces apoptosis upon contact with its Fas/CD95/APO1 receptor. Trimerization of FasL on the surface of effector cells is essential in the binding of the Fas trimer of the target cells. The receptor then recruits an adaptor and caspase-like proteins which lead apoptosis. This paper reports on the fate of FasL in HEp-2 cells committed to apoptosis by induction with campthotecin. Our main results demonstrated that in non-apoptotic cells, FasL aggregates in the cytoplasm forming trimers of 120 kDa. Apoptosis increases the trimeric FasL species, but also induces its dissociation into monomers of 35 kDa. In conclusion, camptothecin appears to perturb the Fas and FasL segregation in the cytoplasm by promoting the transit of FasL to the cell surface, thus fostering a process of autocrine or paracrine apoptosis. FasL is trimerized prior to Fas/FasL complex formation, and after apoptosis, FasL undergoes an intense turnover.

Targeting topoisomerase I: molecular mechanisms and cellular determinants of response to topoisomerase I inhibitors

“…Activation of the extrinsic pathway linked to death receptors and initiated by the proximity-induced activation of caspase 8, and subsequent activation of downstream proteases, cooperate in CPT-induced cell death ( Figure 3 ) [70,71] . Recent reports indicate that CPTs increase de novo synthesis of FAS/FAS-ligand and perturb FAS-ligand segregation in the cytoplasm by promoting the transit of FAS-ligand trimers to the cell surface, thus fostering a process of autocrine or paracrine apoptosis [72,73] .…”

Anti-Fas Antibody Conjugated Nanoparticles Enhancing the Antitumor Effect of Camptothecin by Activating the Fas–FasL Apoptotic Pathway

“…The physicochemical properties, in vitro CPT delivery, cytotoxicity, uptake study, apoptosis degree, and in vivo antitumor efficacy of these combinational NPs were studied. We believe that the combined treatment with anti-Fas antibody and CPT will result in the sensitization of cancer cells to FasL-mediated cytotoxicity, conferring synergistic antitumor effect. , …”

“…We believe that the combined treatment with anti-Fas antibody and CPT will result in the sensitization of cancer cells to FasLmediated cytotoxicity, conferring synergistic antitumor effect. 17,22 2. EXPERIMENTAL SECTION 2.1.…”