Objectives: Parathyroid hormone related protein (PTHrP) has been identified as the major hormone responsible for the syndrome of humoral hypercalcemia of malignancy (HHM). Recent studies have shown that a large number of prostate tumors demonstrate the presence of PTHrP despite the fact that prostate cancer is rarely associated with the HHM syndrome. Other studies have indicated that PTHrP behaves as an early response gene, which stimulates ornithine decarboxylase (ODC) enzyme activity, an enzyme, involved in the biosynthesis of polyamines. It is therefore possible that PTHrP regulates prostate tumor cell proliferation via ODC gene expression.
Methods: In the present study, we evaluated the effects of PTHrP and/or dihydrotestosterone (DHT) treatment on DNA synthesis by thymidine incorporation in androgen-dependent (LnCaP) and androgen-independent (PC3) human prostate adenocarcinoma cell lines. In addition, we utilized Northern blot analysis to investigate the effect of PTHrP [1-34] alone or in combination with DHT on ODC mRNA.
Results: PTHrP [1-34] treatment resulted in an increase in thymidine uptake in PC3 cells by 50%, whereas no such increase was seen in LnCaP cells. However, in the LnCaP cells, in the presence of DHT, PTHrP stimulated DNA synthesis to a level greater than that seen with DHT alone. DHT (10 nM) treatment resulted in an induction of PTHrP as well as ODC mRNAs in the androgen-dependent (LnCaP) but not in androgen-independent (PC3) cell line. PTHrP [1-34] treatment resulted in induction of ODC mRNA in the LnCaP cells. Addition of DHT resulted in a further increase in the ODC mRNA expression.
Conclusions: These data suggest that PTHrP may play a role in prostate cancer cell proliferation and the increased ODC gene expression may be one possible mechanisms responsible for this phenomenon.