Linked Life Data

15336602

Source:http://linkedlifedata.com/resource/pubmed/id/15336602

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2004-8-31
pubmed:abstractText
We have previously reported that high extracellular Ca2+ stimulates parathyroid hormone-related protein (PTHrP) release from human prostate and breast cancer cell lines as well as from H-500 rat Leydig cancer cells, an action mediated by the calcium-sensing receptor (CaR). Activating the CaR leads to phosphorylation of mitogen-activated protein kinases (MAPKs) that participate in PTHrP synthesis and secretion. Because the CaR is a G protein-coupled receptor (GPCR), it is likely to transactivate the epidermal growth factor receptor (EGFR) or the platelet-derived growth factor receptor (PDGFR). In this study, we hypothesized that activation of the CaR transactivates the EGFR or PDGFR, and examined whether transactivation affects PTHrP secretion in PC-3 human prostate cancer cells. Using Western analysis, we observed that an increase in extracellular Ca2+ resulted in delayed activation of extracellular signal-regulated kinase (ERK) in PC-3 cells. Pre-incubation with AG1478 (an EGFR kinase inhibitor) or an EGFR neutralizing antibody inhibited the high Ca2+ -induced phosphorylation of ERK1/2. GM6001, a pan matrix metalloproteinase (MMP) inhibitor, also partially suppressed the ERK activation, but AG1296 (a PDGFR kinase inhibitor) did not. High extracellular Ca2+ stimulates PTHrP release during a 6-h incubation (1.5- to 2.5- and 3- to 4-fold increases in 3.0 and 7.5 mM Ca2+, respectively). When cells were preincubated with AG1478, GM6001, or an antihuman heparin-binding EGF (HB-EGF) antibody, PTHrP secretion was significantly inhibited under basal as well as high Ca2+ conditions, while AG1296 had no effect on PTHrP secretion. Taken together, these findings indicate that activation of the CaR transactivates the EGFR, but not the PDGFR, leading to phosphorylation of ERK1/2 and resultant PTHrP secretion, although CaR-EGFR-ERK might not be the only signaling pathway for PTHrP secretion. This transactivation is most likely mediated by activation of MMP and cleavage of proheparin-binding EGF (proHB-EGF) to HB-EGF.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
8756-3282
pubmed:author
pubmed:issnType
Print
pubmed:volume
35
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
664-72
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed:year
2004
pubmed:articleTitle
Calcium-sensing receptor activation stimulates parathyroid hormone-related protein secretion in prostate cancer cells: role of epidermal growth factor receptor transactivation.
pubmed:affiliation
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine and Membrane Biology Program, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA. syano@rics.bwh.harvard.edu
pubmed:publicationType
Journal Article, Comparative Study, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S.