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Am J Physiol Endocrinol Metab 281: E1267-E1274, 2001;
0193-1849/01 $5.00
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Vol. 281, Issue 6, E1267-E1274, December 2001

Ca2+-sensing receptor expression and PTHrP secretion in PC-3 human prostate cancer cells

Jennifer L. Sanders*, Naibedya Chattopadhyay*, Olga Kifor, Toru Yamaguchi, and Edward M. Brown

Endocrine-Hypertension Division and Membrane Biology Program, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115

Prostate cancer metastasizes frequently to bone. Elevated extracellular calcium concentrations ([Ca2+]o) stimulate parathyroid hormone-related protein (PTHrP) secretion from normal and malignant cells, potentially acting via the [Ca2+]o-sensing receptor (CaR). Because prostate cancers produce PTHrP, if high [Ca2+]o stimulates PTHrP secretion via the CaR, this could initiate a mechanism whereby osteolysis caused by bony metastases of prostate cancer promotes further bone resorption. We investigated whether the prostate cancer cell lines LnCaP and PC-3 express the CaR and whether polycationic CaR agonists stimulate PTHrP release. Both PC-3 and LnCaP prostate cancer cell lines expressed bona fide CaR transcripts by Northern analysis and RT-PCR and CaR protein by immunocytochemistry and Western analysis. The polycationic CaR agonists [Ca2+]o, neomycin, and spermine each concentration dependently stimulated PTHrP secretion from PC-3 cells, as measured by immunoradiometric assay, with maximal, 3.2-, 3.6-, and 4.2-fold increases, respectively. In addition, adenovirus-mediated infection of PC-3 cells with a dominant negative CaR construct attenuated high [Ca2+]o-evoked PTHrP secretion, further supporting the CaR's mediatory role in this process. Finally, pretreating PC-3 cells with transforming growth factor (TGF)-beta 1 augmented both basal and high [Ca2+]o-stimulated PTHrP secretion. Thus, in PTHrP-secreting prostate cancers metastatic to bone, the CaR could initiate a vicious cycle, whereby PTHrP-induced bone resorption releases [Ca2+]o and TGF-beta stored within bone, further increasing PTHrP release and osteolysis.

parathyroid hormone-related protein; ion-sensing receptor; osteolysis; prostate cancer; LnCaP cells; skeletal metastases

* These authors contributed equally to this work.




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