Induction of apoptosis in malignant pleural mesothelioma cells by activation of the Fas (Apo-1/CD95) death-signal pathway.
OBJECTIVE: Although well characterized in several solid tumors, the effects of Fas/Fas ligand interactions in malignant pleural mesothelioma cells have not been defined. The present study was undertaken to examine the functional status of the Fas/Fas ligand pathway in malignant pleural mesothelioma cells and to determine the feasibility of targeting this death-signal pathway for molecular intervention in patients with mesotheliomas. METHODS: Fas expression in primary normal human bronchial epithelial cells and 6 malignant pleural mesothelioma cell lines was quantified by means of flow cytometry. The caspase components of the Fas-mediated apoptotic pathway were evaluated by means of Western blot techniques. Soluble Fas ligand-mediated cytotoxicity and apoptosis were evaluated by means of MTS and TUNEL assays, respectively. Cisplatin (3 microg/mL) and lymphokine-activated killer cells were used to enhance mesothelioma sensitivity to soluble Fas ligand. An H2373 nude mouse xenograft model of malignant pleural mesothelioma was established to assess the in vivo effects of soluble Fas ligand. RESULTS: Four of 6 malignant pleural mesothelioma lines exhibited high levels of Fas expression, and 2 of 4 were inherently susceptible to soluble Fas ligand-mediated cytotoxicity (soluble Fas ligand 50% inhibitory concentration, < 15 ng/mL). Two soluble Fas ligand refractory cell lines (H2052 and H513) exhibited high levels of Fas receptor. Pretreatment with cisplatin resulted in a reduction of 50% inhibitory concentration from infinity to 4.17 +/- 0.14 ng/mL and 10.23 +/- 1.58 ng/mL, respectively. Two additional soluble Fas ligand refractory cell lines (H2595 and REN) expressed low levels of Fas. Exposure of these cells to lymphokine-activated killer cells or lymphokine-activated killer cell-conditioned medium followed by a 24-hour treatment with cisplatin resulted in a significant reduction in 50% inhibitory concentration of soluble Fas ligand and pronounced induction of apoptosis. Intraperitoneally administered soluble Fas ligand mediated regression of H2373 xenografts. CONCLUSION: The Fas/Fas ligand pathway in mesothelioma cells is either intrinsically intact or can be rendered functional with chemotherapeutic agents or immune effector cells. These preclinical data support further evaluation of strategies to enhance Fas-mediated apoptosis in mesotheliomas.
Stewart, JH; Nguyen, DM; Chen, GA; Schrump, DS
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