Prostatic Acid Phosphatase Alters the RANKL/OPG System and Induces Osteoblastic Prostate Cancer Bone Metastases

Prostate cancer (PCa) is unique in its tendency to produce osteoblastic (OB) bone metastases. There are no existing therapies that specifically target the OB phase that affects 90% of men with bone metastatic disease. Prostatic acid phosphatase (PAP) is secreted by PCa cells in OB metastases and increases OB growth, differentiation and bone mineralization. The purpose of this study was to investigate whether PAP effects on OB bone metastases are mediated by autocrine and/or paracrine alterations in the RANK/RANKL/OPG system. To investigate whether PAP modulated these factors and altered the bone reaction, we knocked down PAP expression in VCaP cells and stably overexpressed PAP in PC3M cells, both derived from human PCa bone metastases. We show that knockdown of PAP in VCaP cells decreased OPG while increasing RANK/RANKL expression. Forced overexpression of PAP in PC3M cells had the inverse effect, increasing OPG while decreasing RANK/RANKL expression. Co-culture of PCa cells with MC3T3 pre-osteoblasts also revealed a role for secretory PAP in OB-PCa cross-talk. Reduced PAP expression in VCaP cells decreased MC3T3 proliferation and differentiation and reduced their OPG expression. PAP overexpression in PC3M cells altered the bone phenotype creating osteoblastic rather than osteolytic lesions in vivo utilizing an intratibial model. These findings demonstrate that PAP secreted by PCa cells in osteoblastic bone metastases increases OPG and plays a critical role in the vicious cross-talk between cancer and bone cells. These data suggest that inhibition of secretory PAP may be an effective strategy for PCa osteoblastic bone lesions.

Endocrinology. 2016 Oct 26 [Epub ahead of print]

Alexander Kirschenbaum, Sudeh Izadmehr, Shen Yao, Kieley L O'Connor-Chapman, Alan Huang, Elias M Gregoriades, Shoshana Yakar, Alice C Levine

Department of Urology, Icahn School of Medicine at Mt Sinai, NY, NY 10029., Department of Genetics and Genomic Sciences, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mt Sinai, NY, NY 10029., Division of Endocrinology, Diabetes and Bone Metabolism of the Department of Medicine, Icahn School of Medicine at Mt Sinai, NY, NY 10029., Departments of Basic Science and Craniofacial Biology, NY University College of Dentistry, NY, New York 10010.