Several papers have reported that calcium channel blocking drugs were associated with increased breast cancer risk and worsened prognosis. One of the most common signs of breast tumors is the presence of small deposits of calcium, known as microcalcifications. Therefore, we studied the effect of dihydropyridine nifedipine on selected calcium transport systems in MDA-MB-231 cells, originating from triple negative breast tumor and JIMT1 cells that represent a model of HER2-positive breast cancer, which possesses amplification of HER2 receptor, but cells do not response to HER2 inhibition treatment with trastuzumab. Also, we compared the effect of nifedipine on colorectal DLD1 and ovarian A2780 cancer cells. Both, inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) and type 1 sodium calcium exchanger (NCX1) were upregulated due to nifedipine in DLD1 and A2780 cells, but not in breast cancer MDA-MB-231 and JIMT1 cells. On contrary to MDA-MB-231 and JIMT1 cells, in DLD1 and A2780 cells nifedipine induced apoptosis in a concentration-dependent manner. After NCX1 silencing and subsequent treatment with nifedipine, proliferation was decreased in MDA-MB-231, increased in DLD1 cells, and not changed in JIMT1 cells. Silencing of IP3R1 revealed increase in proliferation in DLD1 and JIMT1 cells, but caused decrease in proliferation in MDA-MB-231 cell line after nifedipine treatment. Interestingly, after nifedipine treatment migration was not significantly affected in any of tested cell lines after NCX1 silencing. Due to IP3R1 silencing, significant decrease in migration occurred in MDA-MB-231 cells after nifedipine treatment, but not in other tested cells. These results support different function of the NCX1 and IP3R1 in the invasiveness of various cancer cells due to nifedipine treatment.
- MeSH
- apoptóza účinky léků genetika MeSH
- blokátory kalciových kanálů farmakologie MeSH
- inositol-1,4,5-trisfosfát - receptory genetika metabolismus MeSH
- kolorektální nádory genetika metabolismus patologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádory prsu genetika metabolismus patologie MeSH
- nádory vaječníků genetika metabolismus patologie MeSH
- nifedipin farmakologie MeSH
- pohyb buněk účinky léků genetika MeSH
- proliferace buněk účinky léků genetika MeSH
- protinádorové látky imunologicky aktivní farmakologie MeSH
- pumpa pro výměnu sodíku a vápníku genetika metabolismus MeSH
- receptor erbB-2 genetika metabolismus MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- RNA interference MeSH
- trastuzumab farmakologie MeSH
- triple-negativní karcinom prsu genetika metabolismus patologie MeSH
- vápníková signalizace účinky léků genetika MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
- MeSH
- celogenomová asociační studie metody MeSH
- dospělí MeSH
- elektrokardiografie metody MeSH
- genetická predispozice k nemoci MeSH
- genotyp MeSH
- jednonukleotidový polymorfismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- myokard metabolismus MeSH
- náhlá srdeční smrt etiologie MeSH
- senioři MeSH
- srdeční arytmie genetika metabolismus MeSH
- srdeční komory metabolismus MeSH
- syndrom dlouhého QT genetika metabolismus MeSH
- vápníková signalizace genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
