This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services 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 Henderson, J. Articles by Kremer, R. Search for Related Content PubMed PubMed Citation Articles by Henderson, J. Articles by Kremer, R.

Dysregulation of Parathyroid Hormone-like Peptide Expression and Secretion in a Keratinocyte Model of Tumor Progression¹

Departments of Medicine and Physiology, McGill University, Montreal, PQ, Canada, and Laboratory of Cellular and Molecular Biology, NIH, National Cancer Institute, Bethesda, Maryland 20892 [J. R.]

Using a human keratinocyte model of tumor progression, we have examined the regulation of gene expression and secretion of a parathyroid hormone-like peptide (PLP) that has been implicated in the pathogenesis of hypercalcemia in cancer. A rapid and transient induction of PLP mRNA in response to serum stimulation was demonstrated in both established (HPK1A) and malignant (HPK1A-ras) cells; however the dose dependent increases were greater in HPK1A than in HPK1A-ras. Significant inhibition of this induction was noted with the addition of 1,25-dihydroxyvitamin D₃ at a lower concentration in HPK1A than in HPK1A-ras. Amino-terminal PLP immunoreactivity and bioactivity correlated well (r = 0.98) when measured in conditioned medium. In the absence of mitogenic stimuli, malignant keratinocytes (HPK1A-ras) secreted significantly more PLP than established (HPK1A) keratinocytes. However, in response to increasing concentrations of epidermal growth factor and fetal bovine serum, PLP release was far greater from HPK1A (maximum 13 x basal) than from HPK1A-ras (maximum 3 x basal) cells. In addition, 1,25-dihydroxyvitamin D₃ was more effective in inhibiting both basal and stimulated PLP secretion in HPK1A than in HPK1A-ras cultures. Reduction of extracellular Ca²⁺ from 2.0 mM to 0.5 mM appeared to be more effective at an early time point in reducing PLP secretion from the established cells compared with the malignant cells. These studies therefore demonstrate a progressive dysregulation of PLP expression and secretion in human keratinocytes in the transformation from established to malignant phenotype and may have important implications for understanding the pathogenetic mechanisms involved in vivo in the development of hypercalcemia in cancer.

¹ This work was supported by Grants MT-10839 and MT-5775 from the Medical Research Council of Canada and by a grant from the National Cancer Institute of Canada. J. H. is a recipient of a studentship from the Medical Research Council of Canada.

² To whom requests for reprints should be addressed, at Calcium Research Laboratory, Royal Victoria Hospital, Room H4.67, 687 Pine Avenue West, Montreal, PQ, H3A 1A1, Canada.

Received 5/13/91. Accepted 10/ 2/91.

This article has been cited by other articles:

				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]

				J. L. Sanders, N. Chattopadhyay, O. Kifor, T. Yamaguchi, and E. M. Brown Ca2+-sensing receptor expression and PTHrP secretion in PC-3 human prostate cancer cells Am J Physiol Endocrinol Metab, December 1, 2001; 281(6): E1267 - E1274. [Abstract] [Full Text] [PDF]

				E. M. Brown and R. J. MacLeod Extracellular Calcium Sensing and Extracellular Calcium Signaling Physiol Rev, January 1, 2001; 81(1): 239 - 297. [Abstract] [Full Text] [PDF]

				J. L. Sanders, N. Chattopadhyay, O. Kifor, T. Yamaguchi, R. R. Butters, and E. M. Brown Extracellular Calcium-Sensing Receptor Expression and Its Potential Role in Regulating Parathyroid Hormone-Related Peptide Secretion in Human Breast Cancer Cell Lines Endocrinology, December 1, 2000; 141(12): 4357 - 4364. [Abstract] [Full Text] [PDF]

				N. Chattopadhyay, C. Evliyaoglu, O. Heese, R. Carroll, J. Sanders, P. Black, and E. M. Brown Regulation of secretion of PTHrP by Ca2+-sensing receptor in human astrocytes, astrocytomas, and meningiomas Am J Physiol Cell Physiol, September 1, 2000; 279(3): C691 - C699. [Abstract] [Full Text] [PDF]

				K. E. Abdaimi, V. Papavasiliou, S. A. Rabbani, J. S. Rhim, D. Goltzman, and R. Kremer Reversal of Hypercalcemia with the Vitamin D Analogue EB1089 in a Human Model of Squamous Cancer Cancer Res., July 1, 1999; 59(14): 3325 - 3328. [Abstract] [Full Text] [PDF]

				K. Meerovitch, S. Wing, and D. Goltzman Preproparathyroid Hormone-related Protein, a Secreted Peptide, Is a Substrate for the Ubiquitin Proteolytic System J. Biol. Chem., March 7, 1997; 272(10): 6706 - 6713. [Abstract] [Full Text] [PDF]

				S. Masuda, V. Byford, R. Kremer, H. L. J. Makin, N. Kubodera, Y. Nishii, A. Okazaki, T. Okano, T. Kobayashi, and G. Jones In Vitro Metabolism of the Vitamin D Analog, 22-Oxacalcitriol, Using Cultured Osteosarcoma, Hepatoma, and Keratinocyte Cell Lines J. Biol. Chem., April 12, 1996; 271(15): 8700 - 8708. [Abstract] [Full Text] [PDF]

				F. J. Dilworth, I. Scott, A. Green, S. Strugnell, Y.-D. Guo, E. A. Roberts, R. Kremer, M. J. Calverley, H. L. J. Makin, and G. Jones Different Mechanisms of Hydroxylation Site Selection by Liver and Kidney Cytochrome P450 Species (CYP27 and CYP24) Involved in Vitamin D Metabolism J. Biol. Chem., July 14, 1995; 270(28): 16766 - 16774. [Abstract] [Full Text] [PDF]