Title:Plumbagin Inhibits Breast Tumor Bone Metastasis and Osteolysis by Modulating the Tumor-Bone Microenvironment
Volume: 12
Issue: 8
Author(s): Z. Li, J. Xiao, X. Wu, W. Li, Z. Yang, J. Xie, L. Xu, X. Cai, Z. Lin, W. Guo, J. Luo and M. Liu
Affiliation:
Keywords:
Plumbagin, breast cancer bone metastasis, osteolysis, microenvironment, tumor-bone interaction, osteolytic metastasis, bisphosphonates, Denosumab, osteoclast function, bone resorption, tumor metastasis, osteoblasts, osteoprotegerin, bone marrow monocyte, osteoclastogenesis.
Abstract: Bone metastasis is a common and serious consequence of breast cancer. Bidirectional interaction
between tumor cells and the bone marrow microenvironment drives a so-called ‘vicious cycle’ that promotes
tumor cell malignancy and stimulates osteolysis. Targeting these interactions and pathways in the tumor-bone
microenvironment has been an encouraging strategy for bone metastasis therapy. In the present study, we
examined the effects of plumbagin on breast cancer bone metastasis. Our data indicated that plumbagin
inhibited cancer cell migration and invasion, suppressed the expression of osteoclast-activating factors, altered
the cancer cell induced RANKL/OPG ratio in osteoblasts, and blocked both cancer cell- and RANKL-stimulated
osteoclastogenesis. In mouse model of bone metastasis, we further demonstrated that plumbagin significantly
repressed breast cancer cell metastasis and osteolysis, inhibited cancer cell induced-osteoclastogenesis and
the secretion of osteoclast-activating factors in vivo. At the molecular level, we found that plumbagin abrogated
RANKL-induced NF-κB and MAPK pathways by blocking RANK association with TRAF6 in
osteoclastogenesis, and by inhibiting the expression of osteoclast-activating factors through the suppression of
NF-κB activity in breast cancer cells. Taken together, our data demonstrate that plumbagin inhibits breast
tumor bone metastasis and osteolysis by modulating the tumor-bone microenvironment and that plumbagin
may serve as a novel agent in the treatment of tumor bone metastasis.
