Distinct regulation of cytoplasmic calcium signals and cell death pathways by different plasma membrane calcium ATPase isoforms in MDA-MB-231 breast cancer cells

Curry, Merril C., Luk, Nicole A., Kenny, Paraic A., Roberts-Thomson, Sarah J. and Monteith, Gregory R. (2012) Distinct regulation of cytoplasmic calcium signals and cell death pathways by different plasma membrane calcium ATPase isoforms in MDA-MB-231 breast cancer cells. Journal of Biological Chemistry, 287 34: 28598-28608. doi:10.1074/jbc.M112.364737

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Author Curry, Merril C.
Luk, Nicole A.
Kenny, Paraic A.
Roberts-Thomson, Sarah J.
Monteith, Gregory R.
Title Distinct regulation of cytoplasmic calcium signals and cell death pathways by different plasma membrane calcium ATPase isoforms in MDA-MB-231 breast cancer cells
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
1083-351X
Publication date 2012-08-17
Sub-type Article (original research)
DOI 10.1074/jbc.M112.364737
Open Access Status File (Author Post-print)
Volume 287
Issue 34
Start page 28598
End page 28608
Total pages 11
Place of publication Bethesda, MD, United States
Publisher American Society for Biochemistry and Molecular Biology
Collection year 2013
Language eng
Formatted abstract
Plasma membrane calcium ATPases (PMCAs) actively extrude Ca2+ from the cell and are essential components in maintaining intracellular Ca2+ homeostasis. There are four PMCA isoforms (PMCA1–4), and alternative splicing of the PMCA genes creates a suite of calcium efflux pumps. The role of these different PMCA isoforms in the control of calcium-regulated cell death pathways and the significance of the expression of multiple isoforms of PMCA in the same cell type are not well understood. In these studies, we assessed the impact of PMCA1 and PMCA4 silencing on cytoplasmic free Ca2+ signals and cell viability in MDA-MB-231 breast cancer cells. The PMCA1 isoform was the predominant regulator of global Ca2+ signals in MDA-MB-231 cells. PMCA4 played only a minor role in the regulation of bulk cytosolic Ca2+, which was more evident at higher Ca2+ loads. Although PMCA1 or PMCA4 knockdown alone had no effect on MDA-MB-231 cell viability, silencing of these isoforms had distinct consequences on caspase-independent (ionomycin) and -dependent (ABT-263) cell death. PMCA1 knockdown augmented necrosis mediated by the Ca2+ ionophore ionomycin, whereas apoptosis mediated by the Bcl-2 inhibitor ABT-263 was enhanced by PMCA4 silencing. PMCA4 silencing was also associated with an inhibition of NFκB nuclear translocation, and an NFκB inhibitor phenocopied the effects of PMCA4 silencing in promoting ABT-263-induced cell death. This study demonstrates distinct roles for PMCA1 and PMCA4 in the regulation of calcium signaling and cell death pathways despite the widespread distribution of these two isoforms. The targeting of some PMCA isoforms may enhance the effectiveness of therapies that act through the promotion of cell death pathways in cancer cells.
Keyword Apoptosis
Breast cancer
Calcium
Calcium ATPase
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Pharmacy Publications
 
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Created: Fri, 24 Aug 2012, 15:14:50 EST by Myrtle Sahabandu on behalf of School of Pharmacy