title: Enhancement of death receptor 4-mediated apoptosis and cytotoxicity in renal cell carcinoma cells by anisomycin.
abstract: Renal cell carcinoma (RCC) is one of the most drug-resistant malignancies, and an effective therapy is lacking for metastatic RCC. Anisomycin is known to inhibit protein synthesis and induce ribotoxic stress. The aim of this study was to explore whether anisomycin enhances the cytotoxic effects of mapatumumab, a human agonistic monoclonal antibody specific for death receptor 4 (DR4), in human RCC cells. We examined the cytotoxicity of anisomycin alone and in combination with mapatumumab in human RCC cell lines and primary RCC cell cultures. RCC cells treated with anisomycin showed cytotoxicity in a dose-dependent manner. Anisomyin in combination with mapatumumab showed a synergistic effect not only in two human RCC cell lines but also in five primary RCC cell cultures. The synergy between anisomycin and mapatumumab for cytotoxicity was also observed for apoptosis. Interestingly, anisomycin significantly increased DR4 expression at both the mRNA and the protein level. Furthermore, the combination-induced cytotoxicity was significantly suppressed by a human recombinant DR4:Fc chimeric protein. The combination of anisomycin and mapatumumab also enhanced the activity of caspases 8 and 3, the downstream molecules of death receptors. These findings indicate that anisomycin sensitizes RCC cells to DR4-mediated apoptosis through the induction of DR4, suggesting that combinational treatment with anisomycin and mapatumumab might represent a novel therapeutic strategy for the treatment of RCC.
authors.affiliation: aDepartment of Urology, Hyogo College of Medicine, Hyogo bDepartment of Urology, Kagawa University Faculty of Medicine, Kagawa, Japan cKey Laboratory of Cancer Prevention and Treatment of Heilongjiang dDepartment of Dermatology, Mudanjiang Medical University, Heilongjiang, China.
authors.forename: Yongnan
authors.initials: Y
authors.lastname: Li
authors.forename: Xiuxian
authors.initials: X
authors.lastname: Wu
authors.forename: Xinghua
authors.initials: X
authors.lastname: Jin
authors.forename: Jiumei
authors.initials: J
authors.lastname: Wang
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Togo
authors.forename: Toru
authors.initials: T
authors.lastname: Suzuki
authors.forename: Takahiko
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yamada
authors.forename: Yukako
authors.initials: Y
authors.lastname: Nakanishi
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kanematsu
authors.forename: Michio
authors.initials: M
authors.lastname: Nojima
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kakehi
authors.forename: Shingo
authors.initials: S
authors.lastname: Yamamoto
mesh_terms: D000841:Anisomycin / Q000008:administration & dosage / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; D000841:Anisomycin; C505530:CASP8 protein, human; D053148:Caspase 3; D053181:Caspase 8; C507357:mapatumumab