CST6 protein and peptides inhibit breast cancer bone metastasis by suppressing CTSB activity and osteoclastogenesis

doi:10.7150/thno.62187

	CST6 protein and peptides inhibit breast cancer bone metastasis by suppressing CTSB activity and osteoclastogenesis
	Li, Xiaoxun 2,3; Liang, Yajun 3; Lian, Cheng 3; Peng, Fangli 3; Xiao, Yansen 3; He, Yunfei 3; Ma, Chengxin 3; Wang, Yuan 3; Zhang, Peiyuan 3; Deng, Yuhan 2
刊名	THERANOSTICS
	2021
卷号	11 期号:20 页码:9821-9832
关键词	Breast cancer Bone metastasis Osteoclastogenesis CST6 Peptide drug
ISSN号	1838-7640
DOI	10.7150/thno.62187
通讯作者	Liu, Tong(liutong@hrbmu.edu.cn) ; Hu, Guohong(ghhu@sibs.ac.cn)
英文摘要	Background: Bone metastasis is a frequent symptom of breast cancer and current targeted therapy has limited efficacy. Osteoclasts play critical roles to drive osteolysis and metastatic outgrowth of tumor cells in bone. Previously we identified CST6 as a secretory protein significantly downregulated in bone-metastatic breast cancer cells. Functional analysis showed that CST6 suppresses breast-to-bone metastasis in animal models. However, the functional mechanism and therapeutic potential of CST6 in bone metastasis is unknown. Methods: Using in vitro osteoclastogenesis and in vivo metastasis assays, we studied the effect and mechanism of extracellular CST6 protein in suppressing osteoclastic niches and bone metastasis of breast cancer. A number of peptides containing the functional domain of CST6 were screened to inhibit bone metastasis. The efficacy, stability and toxicity of CST6 recombinant protein and peptides were evaluated in preclinical metastasis models. Results: We show here that CST6 inhibits osteolytic bone metastasis by inhibiting osteoclastogenesis. Cancer cell-derived CST6 enters osteoclasts by endocytosis and suppresses the cysteine protease CTSB, leading to up-regulation of the CTSB hydrolytic substrate SPHK1. SPHK1 suppresses osteoclast maturation by inhibiting the RANKL-induced p38 activation. Importantly, recombinant CST6 protein effectively suppresses bone metastasis in vitro and in vivo. We further identified several peptides mimicking the function of CST6 to suppress cancer cell-induced osteoclastogenesis and bone metastasis. Pre-clinical analyses of CTS6 recombinant protein and peptides demonstrated their potentials in treatment of breast cancer bone metastasis. Conclusion: These findings reveal the CST6-CTSB-SPHK1 signaling axis in osteoclast differentiation and provide a promising approach to treat bone diseases with CST6-based peptides.
资助项目	National Natural Science Foundation of China[81725017] ; National Natural Science Foundation of China[81872367] ; National Natural Science Foundation of China[82072903] ; Ministry of Science and Technology of China[2017YFA0103502] ; Ministry of Science and Technology of China[2020YFA0112302] ; Shanghai Science and Technology Commission[19XD1404500] ; Heilongjiang Province Natural Science Foundation Joint Guidance[LH2020H125]
WOS关键词	RAY CRYSTAL-STRUCTURE ; CATHEPSIN-B ; CYSTATIN-M ; STRUCTURAL BASIS ; DIFFERENTIATION ; IDENTIFICATION ; INACTIVATION ; PATHWAY ; RANKL ; M/E
WOS研究方向	Research & Experimental Medicine
语种	英语
出版者	IVYSPRING INT PUBL
WOS记录号	WOS:000719160500009
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/298994]
专题	中国科学院上海药物研究所
通讯作者	Liu, Tong; Hu, Guohong
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai, Peoples R China 2.Harbin Med Univ, Dept Breast Surg, Canc Hosp, Harbin, Peoples R China 3.Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Inst Nutr & Hlth, CAS Key Lab Tissue Microenvironm & Tumor, Shanghai, Peoples R China 4.Shanghai Jiao Tong Univ Affiliated Peoples Hosp 6, Dept Orthoped, Shanghai, Peoples R China 5.Novomab Biopharmaceut Inc, Nanjing, Peoples R China
推荐引用方式 GB/T 7714	Li, Xiaoxun,Liang, Yajun,Lian, Cheng,et al. CST6 protein and peptides inhibit breast cancer bone metastasis by suppressing CTSB activity and osteoclastogenesis[J]. THERANOSTICS,2021,11(20):9821-9832.
APA	Li, Xiaoxun.,Liang, Yajun.,Lian, Cheng.,Peng, Fangli.,Xiao, Yansen.,...&Hu, Guohong.(2021).CST6 protein and peptides inhibit breast cancer bone metastasis by suppressing CTSB activity and osteoclastogenesis.THERANOSTICS,11(20),9821-9832.
MLA	Li, Xiaoxun,et al."CST6 protein and peptides inhibit breast cancer bone metastasis by suppressing CTSB activity and osteoclastogenesis".THERANOSTICS 11.20(2021):9821-9832.