Hypericin targets osteoclast and prevents breast cancer-induced bone metastasis via NFATc1 signaling pathway
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Zhengxiao Ouyang1, Xiaoning Guo1, Xia Chen1, Bo Liu1, Qiang Zhang1, Ziqing Yin1, Zanjing Zhai2, Xinhua Qu2, Xuqiang Liu3, Dan Peng1, Yi Shen1, Tang Liu1,* and Qing Zhang1,*
1Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
2Department of Orthopedics, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
3Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Artificial Joints Engineering and Technology Research Center of Jiangxi Province, Nanchang, Jiangxi, P.R. China
*These authors contributed equally to this work
Tang Liu, email: [email protected]
Qing Zhang, email: [email protected]
Keywords: hypericin; osteoclast; bone metastasis; breast cancer; NFATc1
Received: September 03, 2017 Accepted: November 13, 2017 Published: December 04, 2017
Bone is the most common target organ of metastasis of breast cancers. This produces considerable morbidity due to skeletal-related events, and severely reduces the quality of life. Increased osteoclast activity is implicated in breast cancer outgrowth in the bone microenvironment. Our previous observation of an anti-osteoclastic activity of hypericin, a natural plant compound, led us to investigate whether hypericin could inhibit bone metastasis and osteolysis caused by breast cancer. We find that hypericin inhibited the upregulation of osteoclasts stimulated by breast cancer cells. The activity of hypericin on osteoclasts and breast cancer-mediated osteoclastogenesis was associated with the inhibition of NFATc1 signaling pathway and attenuation of Ca2+ oscillation. Furthermore, hypericin suppresses invasion and migration in breast cancer cells, but has little effect on breast cancer-cell induced RANKL/OPG ratio in osteoblast or the expression of osteoclast-activating factors. Administration of hypericin could reduce tumor burden, osteolysis induced by direct inoculation of MDA-MB-231 cells into the bone marrow cavity of the tibia as well as metastasis of bone and improve survival in an experimental metastasis model by intracardiac injection of MDA-MB-231 breast cancer cells. Taken together, these results suggest that hypericin may be a potential natural agent for preventing and treating bone destruction in patients with bone metastasis due to breast cancer.
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