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15-deoxy-δ12,14-prostaglandin j2 inhibits osteolytic breast cancer bone metastasis and estrogen deficiency-induced bone loss

 Ki Rim Kim  ;  Hyun Jeong Kim  ;  Sun Kyoung Lee  ;  Gwang Taek Ma  ;  Kwang Kyun Park  ;  Won Yoon Chung 
 PLOS ONE, Vol.10(4) : e0122764, 2015 
Journal Title
Issue Date
Anilides/pharmacology ; Animals ; Bone Neoplasms/drug therapy ; Bone Neoplasms/pathology* ; Bone Neoplasms/secondary* ; Bone Resorption/drug therapy ; Bone Resorption/metabolism* ; Breast Neoplasms/pathology* ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Survival/drug effects ; Disease Models, Animal ; Estrogens/deficiency* ; Female ; Humans ; Male ; Mice ; Mice, Nude ; Osteoclasts/metabolism ; Osteolysis/drug therapy ; Osteolysis/metabolism ; Osteoprotegerin/metabolism ; Ovariectomy ; PPAR gamma/antagonists & inhibitors ; PPAR gamma/metabolism ; Parathyroid Hormone-Related Protein/biosynthesis ; Prostaglandin D2/analogs & derivatives* ; Prostaglandin D2/pharmacology ; RANK Ligand/metabolism
Breast cancer is the major cause of cancer death in women worldwide. The most common site of metastasis is bone. Bone metastases obstruct the normal bone remodeling process and aberrantly enhance osteoclast-mediated bone resorption, which results in osteolytic lesions. 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is an endogenous ligand of peroxisome proliferator-activated receptor gamma (PPARγ) that has anti-inflammatory and antitumor activity at micromolar concentrations through PPARγ-dependent and/or PPARγ-independent pathways. We investigated the inhibitory activity of 15d-PGJ2 on the bone loss that is associated with breast cancer bone metastasis and estrogen deficiency caused by cancer treatment. 15d-PGJ2 dose-dependently inhibited viability, migration, invasion, and parathyroid hormone-related protein (PTHrP) production in MDA-MB-231 breast cancer cells. 15d-PGJ2 suppressed receptor activator of nuclear factor kappa-B ligand (RANKL) mRNA levels and normalized osteoprotegerin (OPG) mRNA levels in hFOB1.19 osteoblastic cells treated with culture medium from MDA-MB-231 cells or PTHrP, which decreased the RANKL/OPG ratio. 15d-PGJ2 blocked RANKL-induced osteoclastogenesis and inhibited the formation of resorption pits by decreasing the activities of cathepsin K and matrix metalloproteinases, which are secreted by mature osteoclasts. 15d-PGJ2 exerted its effects on breast cancer and bone cells via PPARγ-independent pathways. In Balb/c nu/nu mice that received an intracardiac injection of MDA-MB-231 cells, subcutaneously injected 15d-PGJ2 substantially decreased metastatic progression, cancer cell-mediated bone destruction in femora, tibiae, and mandibles, and serum PTHrP levels. 15d-PGJ2 prevented the destruction of femoral trabecular structures in estrogen-deprived ICR mice as measured by bone morphometric parameters and serum biochemical data. Therefore, 15d-PGJ2 may be beneficial for the prevention and treatment of breast cancer-associated bone diseases.
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2. College of Dentistry (치과대학) > Research Institute (부설연구소) > 1. Journal Papers
2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Hyun-Jeong(김현정) ORCID logo https://orcid.org/0000-0003-4608-2120
Ma, Gwang Taek(마광택)
Park, Kwang Kyun(박광균)
Lee, Sun Kyoung(이선경) ORCID logo https://orcid.org/0000-0002-3707-8050
Chung, Won Yoon(정원윤) ORCID logo https://orcid.org/0000-0001-8428-9005
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