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

Kristiann M. Dougherty, Eric A G Blomme, Amy J. Koh, Janet E. Henderson, Kenneth Pienta, Thomas J. Rosol, Laurie K. McCauley

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6015-6022
Number of pages8
JournalCancer Research
Volume59
Issue number23
StatePublished - Dec 1 1999
Externally publishedYes

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Parathyroid Hormone-Related Protein
Prostate
Carcinoma
Growth
Prostatic Neoplasms
Neoplasms
Cell Line
Parathyroid Hormone
Bone and Bones
Cell Proliferation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Dougherty, K. M., Blomme, E. A. G., Koh, A. J., Henderson, J. E., Pienta, K., Rosol, T. J., & McCauley, L. K. (1999). Parathyroid hormone-related protein as a growth regulator of prostate carcinoma. Cancer Research, 59(23), 6015-6022.

Parathyroid hormone-related protein as a growth regulator of prostate carcinoma. / Dougherty, Kristiann M.; Blomme, Eric A G; Koh, Amy J.; Henderson, Janet E.; Pienta, Kenneth; Rosol, Thomas J.; McCauley, Laurie K.

In: Cancer Research, Vol. 59, No. 23, 01.12.1999, p. 6015-6022.

Research output: Contribution to journalArticle

Dougherty, KM, Blomme, EAG, Koh, AJ, Henderson, JE, Pienta, K, Rosol, TJ & McCauley, LK 1999, 'Parathyroid hormone-related protein as a growth regulator of prostate carcinoma', Cancer Research, vol. 59, no. 23, pp. 6015-6022.
Dougherty KM, Blomme EAG, Koh AJ, Henderson JE, Pienta K, Rosol TJ et al. Parathyroid hormone-related protein as a growth regulator of prostate carcinoma. Cancer Research. 1999 Dec 1;59(23):6015-6022.
Dougherty, Kristiann M. ; Blomme, Eric A G ; Koh, Amy J. ; Henderson, Janet E. ; Pienta, Kenneth ; Rosol, Thomas J. ; McCauley, Laurie K. / Parathyroid hormone-related protein as a growth regulator of prostate carcinoma. In: Cancer Research. 1999 ; Vol. 59, No. 23. pp. 6015-6022.
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abstract = "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.",
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