Prostatic acid phosphatase alters the RANKL/OPG system and induces osteoblastic prostate cancer bone metastases

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

Research output: Contribution to journalArticle

Abstract

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 receptor activator of nuclear factor β-B (RANK)/RANK ligand (RANKL)/ osteoprotegerin (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 inPC3Mcells,bothderivedfromhumanPCAbonemetastases.WeshowthatknockdownofPAPinVCaP cells decreased OPG while increasing RANK/RANKL expression. Forced overexpression of PAP in PC3M cellshadtheinverse effect, increasingOPGwhile decreasingRANK/RANKLexpression. Coculture ofPCA cellswithMC3T3preosteoblasts also revealedarole for secretoryPAPinOB-PCAcross talk.ReducedPAP expression in VCaP cells decreased MC3T3 proliferation and differentiation and reduced their OPG expression. PAP overexpression in PC3M cells altered the bone phenotype creating OB rather than osteolytic lesions in vivo using an intratibial model. These findings demonstrate that PAP secreted by PCA cells in OB 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 OB bone lesions.

Original languageEnglish (US)
Pages (from-to)4526-4533
Number of pages8
JournalEndocrinology
Volume157
Issue number12
DOIs
StatePublished - Dec 2016

ASJC Scopus subject areas

  • Endocrinology

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    Kirschenbaum, A., Izadmehr, S., Yao, S., O'Connor-Chapman, K. L., Huang, A., Gregoriades, E. M., Yakar, S., & Levine, A. C. (2016). Prostatic acid phosphatase alters the RANKL/OPG system and induces osteoblastic prostate cancer bone metastases. Endocrinology, 157(12), 4526-4533. https://doi.org/10.1210/en.2016-1606