This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by M. Dougherty, K. Articles by McCauley, L. K. Search for Related Content PubMed PubMed Citation Articles by M. Dougherty, K. Articles by McCauley, L. K.

Parathyroid Hormone-related Protein as a Growth Regulator of Prostate Carcinoma¹

Department of Periodontics/Prevention/Geriatrics [K. M. D., A. J. K., L. K. M.], University of Michigan Comprehensive Cancer Center [K. J. P.], The University of Michigan, Ann Arbor, Michigan 48109-1078; Department of Medicine, McGill University, Montreal, Quebec, Canada H3T 1EZ [J. E. H.]; and Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210 [E. A. G. B., T. J. R.]

Parathyroid hormone-related protein (PTHrP) is produced by prostate carcinoma cells and tumors, but little is known of its role in prostate carcinogenesis. The goal of this study was to evaluate PTHrP expression in the regulation of prostate carcinoma growth using human and animal models. PTHrP expression was assessed in prostate cancer cell lines in vitro. Seven of nine cell lines produced PTHrP, and increased expression was seen during cell proliferation. The MatLyLu rat prostate carcinoma model was used to determine the effects of PTHrP overexpression on prostate tumor growth. PTHrP overexpression did not alter proliferation of the cells in vitro. However, when PTHrP-overexpressing cells were injected into rat hind limbs, primary tumor growth and tumor size were significantly enhanced as compared with control cells. To evaluate PTHrP in human prostate carcinoma patients, immunohistochemistry was performed on metastatic bone lesions. Immunolocalization of PTHrP protein was found in the cytoplasm and nucleus of cancer cells in the bone microenvironment. Because nuclear localization of PTHrP has been associated with an inhibition of apoptosis, the ability of full-length PTHrP to protect prostate cancer cells from apoptotic stimuli was examined. Cells transfected with full-length PTHrP showed significantly increased cell survival after exposure to apoptotic agents as compared with cells producing no PTHrP (plasmid control) or cells transfected with PTHrP lacking its nuclear localization signal. To determine the mechanism of action of PTHrP in prostate cancer cells, the parathyroid hormone/PTHrP receptor status of the cells was determined. These cell lines did not demonstrate parathyroid hormone/PTHrP receptor-mediated binding of iodinated PTHrP or steady-state receptor message by Northern blot analysis, but they did have a detectable receptor message by reverse transcription-PCR analysis. In summary, PTHrP is expressed in many prostate cancer cell lines in vitro and in metastatic bone lesions in vivo. PTHrP expression positively influences primary tumor size in vivo and protects cells from apoptotic stimuli. These data suggest that PTHrP plays an important role in the promotion of prostate tumor establishment and/or progression.

This article has been cited by other articles:

				R. H. Hastings, P. R. Montgrain, R. Quintana, Y. Rascon, L. J. Deftos, and E. Healy Cell cycle actions of parathyroid hormone-related protein in non-small cell lung carcinoma Am J Physiol Lung Cell Mol Physiol, October 1, 2009; 297(4): L578 - L585. [Abstract] [Full Text] [PDF]

				J. DaSilva, D. Gioeli, M. J. Weber, and S. J. Parsons The Neuroendocrine-Derived Peptide Parathyroid Hormone-Related Protein Promotes Prostate Cancer Cell Growth by Stabilizing the Androgen Receptor Cancer Res., September 15, 2009; 69(18): 7402 - 7411. [Abstract] [Full Text] [PDF]

				V. Bhatia, M. K. Saini, X. Shen, L. X. Bi, S. Qiu, N. L. Weigel, and M. Falzon EB1089 inhibits the parathyroid hormone-related protein-enhanced bone metastasis and xenograft growth of human prostate cancer cells Mol. Cancer Ther., July 1, 2009; 8(7): 1787 - 1798. [Abstract] [Full Text] [PDF]

				X. Li, R. Loberg, J. Liao, C. Ying, L. A. Snyder, K. J. Pienta, and L. K. McCauley A Destructive Cascade Mediated by CCL2 Facilitates Prostate Cancer Growth in Bone Cancer Res., February 15, 2009; 69(4): 1685 - 1692. [Abstract] [Full Text] [PDF]

				R. H. Hastings, A. M.P. Laux, A. Casillas, R. Xu, Z. Lukas, K. Ernstrom, and L. J. Deftos Sex-Specific Survival Advantage with Parathyroid Hormone-Related Protein in Non-Small Cell Lung Carcinoma Patients Clin. Cancer Res., January 15, 2006; 12(2): 499 - 506. [Abstract] [Full Text] [PDF]

				I. Talon, V. Lindner, C. Sourbier, E. Schordan, S. Rothhut, M. Barthelmebs, H. Lang, J.-J. Helwig, and T. Massfelder Antitumor effect of parathyroid hormone-related protein neutralizing antibody in human renal cell carcinoma in vitro and in vivo Carcinogenesis, January 1, 2006; 27(1): 73 - 83. [Abstract] [Full Text] [PDF]

				M. F. McCarty Targeting Multiple Signaling Pathways as a Strategy for Managing Prostate Cancer: Multifocal Signal Modulation Therapy Integr Cancer Ther, December 1, 2004; 3(4): 349 - 380. [Abstract] [PDF]

				Y. Fujinaka, D. Sipula, A. Garcia-Ocana, and R. C. Vasavada Characterization of Mice Doubly Transgenic for Parathyroid Hormone-Related Protein and Murine Placental Lactogen: A Novel Role for Placental Lactogen in Pancreatic {beta}-Cell Survival Diabetes, December 1, 2004; 53(12): 3120 - 3130. [Abstract] [Full Text] [PDF]

				Y.-M. Wu, D. R. Robinson, and H.-J. Kung Signal Pathways in Up-regulation of Chemokines by Tyrosine Kinase MER/NYK in Prostate Cancer Cells Cancer Res., October 15, 2004; 64(20): 7311 - 7320. [Abstract] [Full Text] [PDF]

				N. Shukeir, A. Arakelian, G. Chen, S. Garde, M. Ruiz, C. Panchal, and S. A. Rabbani A Synthetic 15-mer Peptide (PCK3145) Derived from Prostate Secretory Protein Can Reduce Tumor Growth, Experimental Skeletal Metastases, and Malignancy-Associated Hypercalcemia Cancer Res., August 1, 2004; 64(15): 5370 - 5377. [Abstract] [Full Text] [PDF]

				T. Massfelder, H. Lang, E. Schordan, V. Lindner, S. Rothhut, S. Welsch, P. Simon-Assmann, M. Barthelmebs, D. Jacqmin, and J.-J. Helwig Parathyroid Hormone-Related Protein Is an Essential Growth Factor for Human Clear Cell Renal Carcinoma and a Target for the von Hippel-Lindau Tumor Suppressor Gene Cancer Res., January 1, 2004; 64(1): 180 - 188. [Abstract] [Full Text] [PDF]

				R. H. Hastings, F. Araiza, D. W. Burton, L. Zhang, M. Bedley, and L. J. Deftos Parathyroid hormone-related protein ameliorates death receptor-mediated apoptosis in lung cancer cells Am J Physiol Cell Physiol, December 1, 2003; 285(6): C1429 - C1436. [Abstract] [Full Text] [PDF]

				J. C. Mills, N. Andersson, T. S. Stappenbeck, C. C. M. Chen, and J. I. Gordon Molecular Characterization of Mouse Gastric Zymogenic Cells J. Biol. Chem., November 14, 2003; 278(46): 46138 - 46145. [Abstract] [Full Text] [PDF]

				J. Qian, M. C. Colbert, D. Witte, C.-Y. Kuan, E. Gruenstein, H. Osinska, B. Lanske, H. M. Kronenberg, and T. L. Clemens Midgestational Lethality in Mice Lacking the Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Is Associated with Abrupt Cardiomyocyte Death Endocrinology, March 1, 2003; 144(3): 1053 - 1061. [Abstract] [Full Text] [PDF]

				R. J. MacLeod, N. Chattopadhyay, and E. M. Brown PTHrP stimulated by the calcium-sensing receptor requires MAP kinase activation Am J Physiol Endocrinol Metab, February 1, 2003; 284(2): E435 - E442. [Abstract] [Full Text] [PDF]

				A. Cebrian, A. Garcia-Ocana, K. K. Takane, D. Sipula, A. F. Stewart, and R. C. Vasavada Overexpression of Parathyroid Hormone-Related Protein Inhibits Pancreatic {beta}-Cell Death In Vivo and In Vitro Diabetes, October 1, 2002; 51(10): 3003 - 3013. [Abstract] [Full Text] [PDF]

				V. A. Tovar Sepulveda, X. Shen, and M. Falzon Intracrine PTHrP Protects against Serum Starvation-Induced Apoptosis and Regulates the Cell Cycle in MCF-7 Breast Cancer Cells Endocrinology, February 1, 2002; 143(2): 596 - 606. [Abstract] [Full Text] [PDF]

				J. C. Mills, A. J. Syder, C. V. Hong, J. L. Guruge, F. Raaii, and J. I. Gordon A molecular profile of the mouse gastric parietal cell with and without exposure to Helicobacter pylori PNAS, November 20, 2001; 98(24): 13687 - 13692. [Abstract] [Full Text] [PDF]

				V. Richard, M. D. Lairmore, P. L. Green, G. Feuer, R. S. Erbe, B. Albrecht, C. D'Souza, E. T. Keller, J. Dai, and T. J. Rosol Humoral Hypercalcemia of Malignancy : Severe Combined Immunodeficient/Beige Mouse Model of Adult T-Cell Lymphoma Independent of Human T-Cell Lymphotropic Virus Type-1 Tax Expression Am. J. Pathol., June 1, 2001; 158(6): 2219 - 2228. [Abstract] [Full Text] [PDF]

				A. Gujral, D. W. Burton, R. Terkeltaub, and L. J. Deftos Parathyroid Hormone-related Protein Induces Interleukin 8 Production by Prostate Cancer Cells via a Novel Intracrine Mechanism Not Mediated by its Classical Nuclear Localization Sequence Cancer Res., March 1, 2001; 61(5): 2282 - 2288. [Abstract] [Full Text]

				D. E. H. Afar, I. Vivanco, R. S. Hubert, J. Kuo, E. Chen, D. C. Saffran, A. B. Raitano, and A. Jakobovits Catalytic Cleavage of the Androgen-regulated TMPRSS2 Protease Results in Its Secretion by Prostate and Prostate Cancer Epithelia Cancer Res., February 1, 2001; 61(4): 1686 - 1692. [Abstract] [Full Text]

				M. M. Aarts, D. Davidson, A. Corluka, E. Petroulakis, J. Guo, F. R. Bringhurst, J. Galipeau, and J. E. Henderson Parathyroid Hormone-related Protein Promotes Quiescence and Survival of Serum-deprived Chondrocytes by Inhibiting rRNA Synthesis J. Biol. Chem., October 5, 2001; 276(41): 37934 - 37943. [Abstract] [Full Text] [PDF]