Session: FP16-Cancers of Endocrine Organs: Mechanisms of Tumorigenesis & Progression
Room 206 (Moscone Center)
Poster Board SUN-296
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
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