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  • Title: Ca(2+)-sensing receptor expression and PTHrP secretion in PC-3 human prostate cancer cells.
    Author: Sanders JL, Chattopadhyay N, Kifor O, Yamaguchi T, Brown EM.
    Journal: Am J Physiol Endocrinol Metab; 2001 Dec; 281(6):E1267-74. PubMed ID: 11701443.
    Abstract:
    Prostate cancer metastasizes frequently to bone. Elevated extracellular calcium concentrations ([Ca(2+)](o)) stimulate parathyroid hormone-related protein (PTHrP) secretion from normal and malignant cells, potentially acting via the [Ca(2+)](o)-sensing receptor (CaR). Because prostate cancers produce PTHrP, if high [Ca(2+)](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 [Ca(2+)](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 [Ca(2+)](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 [Ca(2+)](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 [Ca(2+)](o) and TGF-beta stored within bone, further increasing PTHrP release and osteolysis.
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