Abstract
Abstract The majority of patients dying from cancer of the breast or prostate have metastases to bone. Bone is a dynamic tissue and metastatic breast cancer cells indirectly induce osteoclast-mediated bone resorption by secreting osteolytic factors, resulting in the increase of bone destruction. 15-deoxy-α12,14-prostaglandin J2 (15d-PGJ2), an endogenous ligand for peroxisome proliferator-activated receptor-α, is the electrophilic cyclopentenone prostaglandin as one of the terminal products of the cyclooxygenase-2-catalyzed reactions. Through the post-translational modification of redox and inflammatory signaling molecules, this prostaglandin exerts various biological actions, such as potent anti-inflammatory, anti-proliferative, anti-fibrotic, and apoptotic activities. In particular, 15d-PGJ2 has been known to exhibit anti-tumor effects in a variety of cancers. This study explores the in vitro and in vivo effect of 15d-PGJ2 on osteolytic bone metastasis by breast cancer cells. 15d-PGJ2 inhibited the migration and invasion of MDA-MB-231 metastatic human breast cancer cells, in a dose-dependent manner. Treatment with 15d-PGJ2 inhibited osteoclast formation and reduced pit formation by osteoclast activity in receptor activator of the NF-κB ligand (RANKL)-treated mouse bone marrow macrophages (BMMs). In differentiated osteoclasts, the activities of matrix metalloproteinases (MMPs) and cathepsin K markedly decreased by 15d-PGJ2 treatment. Furthermore, we inoculated MDA-MB-231 cells into the left cardiac ventricle of nude mice and then subcutaneously injected 15d-PGJ2 for 6 weeks. The histomorphometrical analysis, including bone volume and microstructure, revealed that 15d-PGJ2 inhibited bone destruction by metastatic breast cancer cells. These results demonstrate that 15d-PGJ2 may inhibit migration/invasion of breast cancer cells, prevent RANKL-mediated osteoclast differentiation/ activity, and suppress breast cancer cells-mediated osteolytic lesion in mice. Thus, 15d-PGJ2 can be a therapeutic agent for cancer metastasis to bone. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2571. doi:1538-7445.AM2012-2571
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