PubMed · 16817376
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Hideki Tahara. 2006-06-28. [Hypercalcemic crisis].. https://pubmed.ncbi.nlm.nih.gov/16817376/
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Human calcitonin is the physiological hormone involved in calcium-phosphorus homeostasis. However, its use is limited by its propensity to form aggregates. We find that the type of host lipid has a pronounced influence on human calcitonin fibrillation or incorporation, as assessed by channel formation, in planar lipid membranes at neutral pH. At pH 7, human calcitonin is able to interact and form channels with negatively charged dioleoyl-phosphatidylglycerol (DOPG) bilayers and with zwitterionic palmitoyl-oleoyl phosphatidylcholine (POPC) bilayers containing 15% negatively-charged DOPG, but not with POPC bilayers. At low pH (4.5 and 3.8), the conformational variation of the peptide enables it to insert into POPC and POPC:DOPG but not into DOPG bilayers. The model proposed for human calcitonin interaction and channel formation at acidic pH was based on theoretical predictions of the protonation-deprotonation state of some amino acids, in particular in the fibrillating sequence of peptide molecules; the length of the alpha-helix, and the electrostatic and/or hydrophobic interaction also seem to be relevant. These results may suggest that human calcitonin at low local pH could be involved in osteoclasts' calcium-sensitive permeability through channel formation and/or receptor interaction.
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Calcitonin (CT) is synthesized and secreted in prostate epithelium, and its secretion from malignant prostates is several folds higher than that in benign prostates. CT receptor (CTR) is expressed in malignant prostate epithelium, and its activation increases invasiveness of prostate cancer (PC) cells via activation of protein kinase A. Since the role of urokinase-type plasminogen activator (uPA) in invasion of PC has been established, we tested the hypothesis that CT increases invasion of PC cells by stimulating uPA secretion from PC cells. Exogenously added CT stimulated the secretion of uPA from PC-3M cells in a dose-dependent manner, which was blocked by Rp.cAMP, a competitive inhibitor of protein kinase A. CT stimulated the secretion of MMP-2 and MMP-9 from PC-3M cells, and also increased their invasiveness. Both these actions of CT were blocked by uPA-neutralizing antibodies. Immunofluorescence studies with PC-3M cells suggest that CT stimulated redistribution of cellular uPA to focal adhesion sites, which was further confirmed by co-immunoprecipitation of uPA with focal adhesion kinase (FAK) in response to CT. These results suggest that CT increases invasiveness of PC cells by stimulating PKA-mediated uPA secretion and by redirecting the secreted uPA to focal adhesion sites. The results also suggest that uPA may, at least in part, mediate proinvasive actions of CT on PC cells by stimulating the secretion of gelatinases and degradation of focal adhesion sites.