FP16-1 PROSTATIC ACID PHOSPHATASE IN PROSTATE CANCER BONE METASTASES: RANK LIGAND AS A MEDIATOR

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP16-Cancers of Endocrine Organs: Mechanisms of Tumorigenesis & Progression
Basic/Translational
Sunday, June 16, 2013: 10:45 AM-11:15 AM
Presentation Start Time: 10:45 AM
Room 206 (Moscone Center)

Poster Board SUN-296
Alexander Kirschenbaum1, Sudeh Izadmehr2, Grace Liao3, Amanda Leiter3, Wei Yang3, Shen Yao3 and Alice C Levine*4
1Mount Sinai School of Medicine, New York, 2Mount Sinai School of Medicine, New York, NY, 3Mount Sinai School of Medicine, 4Mt Sinai Med Ctr, New York, NY
BACKGROUND: Bone metastases are the major cause of morbidity and mortality in prostate cancer (PCa). While there are treatments for the osteolytic phase of PCa bone metastases, there are no therapies that inhibit the later osteoblastic phase. Prostatic acid phosphatase (PAP) is a protein secreted by PCa cells and is highly expressed in PCa osteoblastic bone metastases. We previously demonstrated that PAP secreted by PCa cells induces the proliferation and differentiation of osteoblasts (OB).  OB mediate osteoclast differentiation and function by secreting two proteins, RANK Ligand (RANKL) and Osteoprotegerin (OPG). RANKL promotes osteoclastic activity when bound to the RANK receptor on osteoclasts and OPG is a decoy receptor that binds to RANKL and inhibits the activation of osteoclasts.

Hypothesis: In addition to directly inhibiting OB differentiation, we hypothesize that PCa-derived PAP modulates the RANKL/OPG system in PCa bone metastases favoring an osteoblastic bone phenotype.

METHODS: Two human PCa cell lines, VCaP (PAP+) and PC3 (PAP-) as well as a mouse preosteoblast (OB) line, MC3T3 were studied. PC3 cells were stably transfected to overexpress PAP while VCaP cells were transiently transfected with siPAP to knockdown expression. To assess if the enzymatic effect of PAP is reversible by L-tartrate, an inhibitor of PAP, was added to parental VCaP and PC3 cells and conditioned medium (CM) from the PCa cell lines +/- L-tartrate were added to MC3T3 OB cultures. RANKL and OPG mRNA/protein expression was assessed with RT-PCR, western blot and immunohistochemistry.

RESULTS: All three cell lines (MC3T3, PC3 and VCaP) expressed measurable amounts of RANKL and OPG mRNA/protein.  PAP overexpression in PC3 cells increased OPG protein, and knockdown in VCaP cells decreased OPG.    Treatment with L-tartrate had no effect on RANKL/OPG expression in the PAP- PC3 line but increased OPG and decreased RANKL in VCaP cells.  Finally, conditioned medium from VCaP (PAP+) cells inhibited the expression of RANKL by MC3T3 preosteoblasts and this was reversed by the addition of L-tartrate.

CONCLUSIONS: Our results suggest that PAP secreted by PCa cells in bone metastases modulates RANKL/OPG expression in both PCa and OB cells.  The overall effect of PAP is to increase OPG and decrease RANKL thereby favoring the osteoblastic phenotype. Therapies that target PAP may be effective for the treatment of the OB phase of PCa bone metastases.

Nothing to Disclose: AK, SI, GL, AL, WY, SY, ACL

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Department of Defense Exploration Hypothesis Award
Previous Abstract | Next Abstract >>