TY - JOUR
T1 - Spleen tyrosine kinase (SYK) inhibitor PRT062607 protects against ovariectomy-induced bone loss and breast cancer-induced bone destruction
AU - Xie, Gang
AU - Liu, Wenjie
AU - Lian, Zhen
AU - Xie, Dantao
AU - Yuan, Guixin
AU - Ye, Jiajie
AU - Lin, Zihong
AU - Wang, Weidong
AU - Zeng, Jican
AU - Shen, Huaxing
AU - Wang, Xinjia
AU - Feng, Haotian
AU - Cong, Wei
AU - Yao, Guanfeng
PY - 2021/6
Y1 - 2021/6
N2 - Osteolytic diseases, including breast cancer-induced osteolysis and postmenopausal osteoporosis, are attributed to excessive bone resorption by osteoclasts. Spleen tyrosine kinase (SYK) is involved in osteoclastogenesis and bone resorption, whose role in breast cancer though remains controversial. Effects of PRT062607 (PRT), a highly specific inhibitor of SYK, on the osteoclast and breast cancer functionalities are yet to be clarified. This study demonstrated the in vitro inhibitory actions of PRT on the osteoclast-specific gene expression, bone resorption, and osteoclastogenesis caused by receptor activator of nuclear factor kappa B ligand (RANKL), as well as its in vitro suppressive effects on the growth, migration and invasion of breast carcinoma cell line MDA-MB-231, which were achieved through PLCγ2 and PI3K-AKT-mTOR pathways. Further, we proved that PRT could prevent post-ovariectomy (OVX) loss of bone and breast cancer-induced bone destruction in vivo, which agreed with the in vitro outcomes. In conclusion, our findings suggest the potential value of PRT in managing osteolytic diseases mediated by osteoclasts.
AB - Osteolytic diseases, including breast cancer-induced osteolysis and postmenopausal osteoporosis, are attributed to excessive bone resorption by osteoclasts. Spleen tyrosine kinase (SYK) is involved in osteoclastogenesis and bone resorption, whose role in breast cancer though remains controversial. Effects of PRT062607 (PRT), a highly specific inhibitor of SYK, on the osteoclast and breast cancer functionalities are yet to be clarified. This study demonstrated the in vitro inhibitory actions of PRT on the osteoclast-specific gene expression, bone resorption, and osteoclastogenesis caused by receptor activator of nuclear factor kappa B ligand (RANKL), as well as its in vitro suppressive effects on the growth, migration and invasion of breast carcinoma cell line MDA-MB-231, which were achieved through PLCγ2 and PI3K-AKT-mTOR pathways. Further, we proved that PRT could prevent post-ovariectomy (OVX) loss of bone and breast cancer-induced bone destruction in vivo, which agreed with the in vitro outcomes. In conclusion, our findings suggest the potential value of PRT in managing osteolytic diseases mediated by osteoclasts.
KW - mTOR
KW - Osteoclast
KW - PLCγ2
KW - PRT062607
KW - Spleen tyrosine kinase
UR - http://www.scopus.com/inward/record.url?scp=85105321290&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2021.114579
DO - 10.1016/j.bcp.2021.114579
M3 - Article
C2 - 33895161
AN - SCOPUS:85105321290
VL - 188
JO - Journal of Biochemical Pharmacology
JF - Journal of Biochemical Pharmacology
SN - 0006-2952
M1 - 114579
ER -