Ca(2+)-sensing receptor expression and PTHrP secretion in PC-3 human prostate cancer cells.
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.
Sanders
J L
JL
Endocrine-Hypertension Division and Membrane Biology Program, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Chattopadhyay
N
N
Kifor
O
O
Yamaguchi
T
T
Brown
E M
EM
D000257:Adenoviridae Infections / Q000235:genetics; D015152:Blotting, Northern; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D010281:Parathyroid Hormone / Q000378:metabolism*; D044162:Parathyroid Hormone-Related Protein; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
C470121:PTHLH protein, human; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D012333:RNA, Messenger; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface; D002118:Calcium