Fas-mediated signaling enhances sensitivity of human soft tissue sarcoma cells to anticancer drugs by activation of p38 kinase.
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.
Li
WeiWei
W
Program of Molecular Pharmacology and Chemistry, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Bertino
Joseph R
JR
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
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