title: Plumbagin inhibits breast tumor bone metastasis and osteolysis by modulating the tumor-bone microenvironment.
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.
authors.affiliation: East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.forename: J
authors.initials: J
authors.lastname: Xiao
authors.forename: X
authors.initials: X
authors.lastname: Wu
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.forename: Z
authors.initials: Z
authors.lastname: Yang
authors.forename: J
authors.initials: J
authors.lastname: Xie
authors.forename: L
authors.initials: L
authors.lastname: Xu
authors.forename: X
authors.initials: X
authors.lastname: Cai
authors.forename: Z
authors.initials: Z
authors.lastname: Lin
authors.forename: W
authors.initials: W
authors.lastname: Guo
authors.forename: J
authors.initials: J
authors.lastname: Luo
authors.forename: M
authors.initials: M
authors.lastname: Liu
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D050071:Bone Density Conservation Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000556:secondary; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology; D001943:Breast Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009285:Naphthoquinones / Q000494:pharmacology* / Q000627:therapeutic use; D009361:Neoplasm Invasiveness; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010014:Osteolysis / Q000188:drug therapy* / Q000209:etiology; D011485:Protein Binding; D053245:RANK Ligand / Q000378:metabolism / Q000502:physiology; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000199:Actins; D000943:Antigens, Differentiation; D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D016207:Cytokines; D016328:NF-kappa B; D009285:Naphthoquinones; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D048029:TNF Receptor-Associated Factor 6; C505686:TNFRSF11A protein, human; D020928:Mitogen-Activated Protein Kinases; C014758:plumbagin