1. Enhancement of death receptor 4-mediated apoptosis and cytotoxicity in renal cell carcinoma cells by anisomycin
- Author
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Shingo Yamamoto, Yoshiyuki Kakehi, Yoshikazu Togo, Jiumei Wang, Michio Nojima, Yongnan Li, Xiu-Xian Wu, Takahiko Hashimoto, Xinghua Jin, Akihiro Kanematsu, Yusuke Yamada, Yukako Nakanishi, and Toru Suzuki
- Subjects
0301 basic medicine ,Cancer Research ,Apoptosis ,Antibodies, Monoclonal, Humanized ,urologic and male genital diseases ,Caspase 8 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Cytotoxic T cell ,Pharmacology (medical) ,Cytotoxicity ,Carcinoma, Renal Cell ,neoplasms ,Caspase ,Anisomycin ,Pharmacology ,biology ,Caspase 3 ,Chemistry ,Antibodies, Monoclonal ,Drug Synergism ,Kidney Neoplasms ,female genital diseases and pregnancy complications ,Enzyme Activation ,Receptors, TNF-Related Apoptosis-Inducing Ligand ,030104 developmental biology ,Oncology ,Cell culture ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Mapatumumab ,medicine.drug - 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.
- Published
- 2017