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ß2-Microglobulin Is a Signaling and Growth-Promoting Factor for Human Prostate Cancer Bone Metastasis

¹ Molecular Urology and Therapeutics Program, Department of Urology and Winship Cancer Institute, ² Microchemical and Proteomics Facility, and ³ Divison of Endocrinology and Metabolism and Lipids, Emory University School of Medicine, Atlanta, Georgia; ⁴ Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama; and ⁵ Department of Biological Science, University of Delaware, Newark, Delaware

Requests for reprints: Leland W.K. Chung, Molecular Urology and Therapeutics Program, Department of Urology and Winship Cancer Institute, Emory University School of Medicine, 1365-B Clifton Road, Room B5101, Atlanta, GA 30322. Phone: 404-778-3672; Fax: 404-778-3675; E-mail: lwchung{at}emory.edu.

The protein factor ß2-microglobulin (ß2M), purified from the conditioned medium of human prostate cancer cell lines, stimulated growth and enhanced osteocalcin (OC) and bone sialoprotein (BSP) gene expression in human prostate cancer cells by activating a cyclic AMP (cAMP)–dependent protein kinase A signaling pathway. When ß2M was overexpressed in prostate cancer cells, it induced explosive tumor growth in mouse bone through increased phosphorylated cAMP-responsive element binding protein (CREB) and activated CREB target gene expression, including OC, BSP, cyclin A, cyclin D1, and vascular endothelial growth factor. Interrupting the ß2M downstream signaling pathway by injection of the ß2M small interfering RNA liposome complex produced an effective regression of previously established prostate tumors in mouse bone through increased apoptosis as shown by immunohistochemistry and activation of caspase-9, caspase-3, and cleavage of poly(ADP-ribose) polymerase. These results suggest that ß2M signaling is an attractive new therapeutic target for the treatment of lethal prostate cancer bone metastasis. (Cancer Res 2006; 66(18): 9108-16)

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