Histone deacetylase inhibitor- and PMA-induced upregulation of PMCA4b enhances Ca2+ clearance from MCF-7 breast cancer cells.
The expression of the plasma membrane Ca2+ ATPase (PMCA) isoforms is altered in several types of cancer cells suggesting that they are involved in cancer progression. In this study we induced differentiation of MCF-7 breast cancer cells by histone deacetylase inhibitors (HDACis) such as short chain fatty acids (SCFAs) or suberoylanilide hydroxamic acid (SAHA), and by phorbol 12-myristate 13-acetate (PMA) and found strong upregulation of PMCA4b protein expression in response to these treatments. Furthermore, combination of HDACis with PMA augmented cell differentiation and further enhanced PMCA4b expression both at mRNA and protein levels. Immunocytochemical analysis revealed that the upregulated protein was located mostly in the plasma membrane. To examine the functional consequences of elevated PMCA4b expression, the characteristics of intracellular Ca2+ signals were investigated before and after differentiation inducing treatments, and also in cells overexpressing PMCA4b. The increased PMCA4b expression - either by treatment or overexpression - led to enhanced Ca2+ clearance from the stimulated cells. We found pronounced PMCA4 protein expression in normal breast tissue samples highlighting the importance of this pump for the maintenance of mammary epithelial Ca2+ homeostasis. These results suggest that modulation of Ca2+ signaling by enhanced PMCA4b expression may contribute to normal development of breast epithelium and may be lost in cancer.
Institute of Molecular Pharmacology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
Karolina
K
Varga
Molecular Biophysics Research Group of the Hungarian Academy of Sciences, Department of Biophysics, Semmelweis University, Budapest, Hungary.
Katalin
K
Pászty
Department of Molecular Cell Biology, Hungarian National Blood Transfusion Service, Budapest, Hungary.
Rita
R
Padányi
Institute of Molecular Pharmacology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
Luca
L
Hegedűs
Service d'Anatomie et Cytologie Pathologiques, Hôpital Lariboisière, Paris, France.
Jean-Philippe
JP
Brouland
Institut National de la Santé et de la Recherche Médicale, U978, Bobigny, France; Université Paris-13, PRES Sorbonne Paris-Cité, Bobigny, France.
Béla
B
Papp
Institute of Molecular Pharmacology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary; Department of Molecular Cell Biology, Hungarian National Blood Transfusion Service, Budapest, Hungary. Electronic address: enyedi@biomembrane.hu.
Agnes
A
Enyedi
D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D061986:MCF-7 Cells; D008301:Maleimides / Q000494:pharmacology; D010421:Pentanoic Acids / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology*; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*; D000077337:Vorinostat
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D008301:Maleimides; D010421:Pentanoic Acids; D010703:Phorbol Esters; D020033:Protein Isoforms; D012333:RNA, Messenger; C119222:phorbol-12-myristate; D000077337:Vorinostat; C507517:ATP2B4 protein, human; D053499:Plasma Membrane Calcium-Transporting ATPases; C038780:n-pentanoic acid; C070515:bisindolylmaleimide I; D002118:Calcium
Breast cancer; Ca(2+) signaling; Differentiation; Mammary epithelium; Plasma membrane Ca(2+) ATPase; Store operated Ca(2+) entry