title: Activation of unfolded protein response protects osteosarcoma cells from cisplatin-induced apoptosis through NF-κB pathway.
abstract: The aim of this study was to uncover that unfolded protein response (UPR) contributed to the development of cisplatin resistance in osteosarcoma. MG-63 cells and SaOS-2 cells were exposed to cisplatin at presence or absence of 4-phenylbutyrayte (4-pba) and then analyzed by MTT assay and flow cytometry to determine the cell survival rates and apoptosis. Levels of glucose regulated protein 78KD (GRP78), C/EBP homologus protein (CHOP), cytoplasmic and nuclear NF-κB were detected by Western blot. Further, MG-63 cells and SaOS-2 cells were subjected to cisplatin with or without Bay 11-7082, a well-known inhibitor of NF-κB. After that, MTT assay and flow cytometry were used to determine the cell survival rates and apoptosis. Cisplatin and 4-PBA co-treatment significantly enhanced the cell apoptosis. Administration of cisplatin substantially increased the levels of GRP78 and CHOP. Moreover, mechanistic investigation uncovered that cisplatin promoted the levels of nuclear NF-κB whereas 4-PBA administration suppressed the cisplatin-induced accumulation of nuclear NF-κB level in osteosarcoma cells. Cisplatin combined with Bay 11-7082 obviously augmented MG-63 cells and SaOS-2 cells apoptosis when compared to that in osteosarcoma cells treated by cisplatin alone. Taken together, our data show that UPR protects osteosarcoma from cisplatin-mediated apoptosis through activation of NF-κB pathway. Therefore, targeting UPR may be a potential strategy to improve the osteosarcoma therapy.
authors.affiliation: Department of Orthopeadic Surgery, The Second Xiangya Hospital, Central South University Changsha, Hunan, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Yan
authors.affiliation: Department of Orthopeadic Surgery, The Second Xiangya Hospital, Central South University Changsha, Hunan, China.
authors.forename: Jiangdong
authors.initials: J
authors.lastname: Ni
authors.affiliation: Department of Orthopeadic Surgery, The Second Xiangya Hospital, Central South University Changsha, Hunan, China.
authors.forename: Deye
authors.initials: D
authors.lastname: Song
authors.affiliation: Department of Orthopeadic Surgery, The Second Xiangya Hospital, Central South University Changsha, Hunan, China.
authors.forename: Muliang
authors.initials: M
authors.lastname: Ding
authors.affiliation: Department of Orthopeadic Surgery, The Second Xiangya Hospital, Central South University Changsha, Hunan, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Huang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D012516:Osteosarcoma / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D056811:Unfolded Protein Response / Q000187:drug effects / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D016328:NF-kappa B; D002945:Cisplatin
keywords: NF-κB; Osteosarcoma; UPR; chemoresistance; cisplatin