CST6 protein and peptides inhibit breast cancer bone metastasis by suppressing CTSB activity and osteoclastogenesis
| Autor: | Yuhan Deng, Fangli Peng, Peiyuan Zhang, Xiangyin Kong, Guohong Hu, Chengxin Ma, Yuan Wang, Xiaoxun Li, Tong Liu, Yunfei He, Yansen Xiao, Yajun Liang, Yunpeng Su, Qingcheng Yang, Cheng Lian, Cheng Luo |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Osteolysis
Osteoclastogenesis medicine.medical_treatment Medicine (miscellaneous) Osteoclasts Bone Neoplasms Breast Neoplasms Bone and Bones Targeted therapy Metastasis Cathepsin B Osteoclast maturation Mice Breast cancer Osteoclast Osteogenesis Cell Line Tumor medicine Animals Humans Breast Neoplasm Metastasis Pharmacology Toxicology and Pharmaceutics (miscellaneous) Mice Inbred BALB C Chemistry Cystatin M Macrophages NF-kappa B Cancer Bone metastasis CST6 medicine.disease Cathepsins medicine.anatomical_structure Peptide drug Cancer research Female Research Paper Signal Transduction |
| Zdroj: | Theranostics |
| ISSN: | 1838-7640 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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