title: Bortezomib Inhibits Giant Cell Tumor of Bone through Induction of Cell Apoptosis and Inhibition of Osteoclast Recruitment, Giant Cell Formation, and Bone Resorption.
abstract: Giant cell tumor of bone (GCTB) is a rare and highly osteolytic bone tumor that usually leads to an extensive bone lesion. The purpose of this study was to discover novel therapeutic targets and identify potential agents for treating GCTB. After screening the serum cytokine profiles in 52 GCTB patients and 10 normal individuals using the ELISA assay, we found that NF-κB signaling-related cytokines, including TNFα, MCP-1, IL1α, and IL17A, were significantly increased in GCTB patients. The results were confirmed by IHC that the expression and activity of p65 were significantly increased in GCTB patients. Moreover, all of the NF-κB inhibitors tested suppressed GCTB cell growth, and bortezomib (Velcade), a well-known proteasome inhibitor, was the most potent inhibitor in blocking GCTB cells growth. Our results showed that bortezomib not only induced GCTB neoplastic stromal cell (NSC) apoptosis, but also suppressed GCTB NSC-induced giant cell differentiation, formation, and resorption. Moreover, bortezomib specifically suppressed GCTB NSC-induced preosteoclast recruitment. Furthermore, bortezomib ameliorated GCTB cell-induced bone destruction in vivo As a result, bortezomib suppressed NF-κB-regulated gene expression in GCTB NSC apoptosis, monocyte migration, angiogenesis, and osteoclastogenesis. Particularly, the inhibitory effects of bortezomib were much better than zoledronic acid, a drug currently used in treating GCTB, in our in vitro experimental paradigms. Together, our results demonstrated that NF-κB signaling pathway is highly activated in GCTB, and bortezomib could suppress GCTB and osteolysis in vivo and in vitro, indicating that bortezomib is a potential agent in the treatment of GCTB. Mol Cancer Ther; 15(5); 854-65. ©2016 AACR.
authors: Shanghai Key Laboratory of Regulatory Biology, Shanghai Changzheng Hospital and East China Normal University Joint Research Center for Orthopedic Oncology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, P.R. China. Department of Orthopedic Oncology, Shanghai Changzheng Hospital and East China Normal University Joint Research Center for Orthopedic Oncology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, P.R. China. Xiamen Hospital of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine. Xiamen, P.R. China.
authors: Leqin
authors: L
authors: Xu
authors: Shanghai Key Laboratory of Regulatory Biology, Shanghai Changzheng Hospital and East China Normal University Joint Research Center for Orthopedic Oncology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, P.R. China. Department of Orthopedic Oncology, Shanghai Changzheng Hospital and East China Normal University Joint Research Center for Orthopedic Oncology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, P.R. China. jluo@bio.ecnu.edu.cn jianruxiao83@163.com.
authors: Jian
authors: J
authors: Luo
authors: Shanghai Key Laboratory of Regulatory Biology, Shanghai Changzheng Hospital and East China Normal University Joint Research Center for Orthopedic Oncology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, P.R. China.
authors: Rongrong
authors: R
authors: Jin
authors: Shanghai Key Laboratory of Regulatory Biology, Shanghai Changzheng Hospital and East China Normal University Joint Research Center for Orthopedic Oncology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, P.R. China.
authors: Zhiying
authors: Z
authors: Yue
authors: Shanghai Key Laboratory of Regulatory Biology, Shanghai Changzheng Hospital and East China Normal University Joint Research Center for Orthopedic Oncology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, P.R. China. The Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai, P.R. China.
authors: Peng
authors: P
authors: Sun
authors: Shanghai Key Laboratory of Regulatory Biology, Shanghai Changzheng Hospital and East China Normal University Joint Research Center for Orthopedic Oncology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, P.R. China.
authors: Zhengfeng
authors: Z
authors: Yang
authors: Department of Orthopedic Oncology, Shanghai Changzheng Hospital and East China Normal University Joint Research Center for Orthopedic Oncology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, P.R. China.
authors: Xinghai
authors: X
authors: Yang
authors: Department of Orthopedic Oncology, Shanghai Changzheng Hospital and East China Normal University Joint Research Center for Orthopedic Oncology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, P.R. China.
authors: Wei
authors: W
authors: Wan
authors: Department of Orthopedic Oncology, Shanghai Changzheng Hospital and East China Normal University Joint Research Center for Orthopedic Oncology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, P.R. China.
authors: Jishen
authors: J
authors: Zhang
authors: The Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai, P.R. China.
authors: Shichang
authors: S
authors: Li
authors: Shanghai Key Laboratory of Regulatory Biology, Shanghai Changzheng Hospital and East China Normal University Joint Research Center for Orthopedic Oncology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, P.R. China. Department of Orthopedic Oncology, Shanghai Changzheng Hospital and East China Normal University Joint Research Center for Orthopedic Oncology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, P.R. China. Department of Molecular and Cellular Medicine, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas.
authors: Mingyao
authors: M
authors: Liu
authors: Shanghai Key Laboratory of Regulatory Biology, Shanghai Changzheng Hospital and East China Normal University Joint Research Center for Orthopedic Oncology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, P.R. China. Department of Orthopedic Oncology, Shanghai Changzheng Hospital and East China Normal University Joint Research Center for Orthopedic Oncology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, P.R. China. jluo@bio.ecnu.edu.cn jianruxiao83@163.com.
authors: Jianru
authors: J
authors: Xiao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D001862:Bone Resorption / Q000188:drug therapy / Q000378:metabolism*; D000069286:Bortezomib / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018212:Giant Cell Tumor of Bone / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism*; D010014:Osteolysis / Q000188:drug therapy / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D000069286:Bortezomib