Parathyroid hormone-related protein as a growth regulator of prostate carcinoma

Parathyroid hormone-related protein (PTHrP) is produced by prostate carcino ma cells and tumors, but little is known of its role in prostate carcinogen esis. The goal of this study was to evaluate PTHrP expression in the regula tion of prostate carcinoma growth using human and animal models. PTHrP expr ession was assessed in prostate cancer cell lines in vitro. Seven of nine c ell lines produced PTHrP, and increased expression was seen during cell pro liferation. The MatLyLu rat prostate carcinoma model was used to determine the effects of PTHrP overexpression on prostate tumor growth. PTHrP overexp ression did not alter proliferation of the cells in vitro, However, when PT HrP-overexpressing cells were injected into rat hind limbs, primary tumor g rowth and tumor size were significantly enhanced as compared with control c ells. To evaluate PTHrP in human prostate carcinoma patients, immunohistoch emistry was performed on metastatic bone lesions. Immunolocalization of PTH rP protein was found in the cytoplasm and nucleus of cancer cells in the bo ne microenvironment. Because nuclear localization of PTHrP has been associa ted with an inhibition of apoptosis, the ability of full-length PTHrP to pr otect prostate cancer cells from apoptotic stimuli was examined. Cells tran sfected with full-length PTHrP showed significantly increased cell survival after exposure to apoptotic agents as compared with cells producing no PTH rP (plasmid control) or cells transfected with PTHrP lacking its nuclear lo calization signal. To determine the mechanism of action of PTHrP in prostat e cancer cells, the parathyroid hormone/PTHrP receptor status of the cells was determined. These cell lines did not demonstrate parathyroid hormone/PT HrP receptor-mediated binding of iodinated PTHrP or steady-state receptor m essage by Northern blot analysis, but they did have a detectable receptor m essage by reverse transcription-PCR analysis. In summary, PTHrP Is expresse d in many prostate cancer cell lines in vitro and in metastatic bone lesion s in vivo. PTHrP expression positively influences primary tumor size in viv o and protects cells from apoptotic stimuli. These data suggest that PTHrP plays an important role in the promotion of prostate tumor establishment an d/or progression.