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Mol Cancer Ther. 2016 May;15(5):854-65. doi: 10.1158/1535-7163.MCT-15-0669. Epub 2016 Feb 9.

Bortezomib Inhibits Giant Cell Tumor of Bone through Induction of Cell Apoptosis and Inhibition of Osteoclast Recruitment, Giant Cell Formation, and Bone Resorption.

Author information

1
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.
2
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.
3
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.
4
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.
5
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.
6
The Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai, P.R. China.
7
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.

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.

PMID:
26861247
DOI:
10.1158/1535-7163.MCT-15-0669
[Indexed for MEDLINE]
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