title: Fas-mediated signaling enhances sensitivity of human soft tissue sarcoma cells to anticancer drugs by activation of p38 kinase.
abstract: Sensitivity of human soft tissue sarcoma (STS) cells to methotrexate, doxorubicin, and paclitaxel was examined after cells were pretreated with CH-11, an agonistic anti-Fas antibody. A subtoxic dose (6 ng/ml) of CH-11 sensitized STS cells but not normal fibroblast cells to these anticancer drugs. CH-11 increased cytochrome c release and consequent activation of caspase-9, independent of caspase-8 and increased p38 activation. Addition of SB203580, a specific inhibitor of p38, resulted in a decrease in activation of this kinase and abrogation of enhanced chemosensitivity (doxorubicin and paclitaxel) by CH-11. These results demonstrate that stimulation of the Fas pathway by a subtoxic dose of a Fas agonist can selectively enhance sensitivity of STS cells to certain chemotherapeutic agents through activation of p38.
authors.affiliation: Program of Molecular Pharmacology and Chemistry, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: WeiWei
authors.initials: W
authors.lastname: Li
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Bertino
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D015153:Blotting, Western; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle; D016923:Cell Death; D002469:Cell Separation; D002599:Chalcone / Q000031:analogs & derivatives* / Q000494:pharmacology; D047188:Chalcones; D003574:Cytochrome c Group / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004789:Enzyme Activation; D005434:Flow Cytometry; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012509:Sarcoma / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D012983:Soft Tissue Neoplasms / Q000378:metabolism* / Q000473:pathology*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: C418965:4-dimethylamino-3',4'-dimethoxychalcone; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D047188:Chalcones; D003574:Cytochrome c Group; D007093:Imidazoles; D011725:Pyridines; D019014:fas Receptor; D002599:Chalcone; D004317:Doxorubicin; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases; C093642:SB 203580; D017239:Paclitaxel