Disruption of the interaction between PMCA2 and calcineurin triggers apoptosis and enhances paclitaxel-induced cytotoxicity in breast cancer cells

Rhiannon R. Baggott, Tamer M.A. Mohamed, Delvac Oceandy, Marylouisa Holton, Marie C. Blanc, Sandrine C. Roux-Soro, Sarah Brown, James E Brown, Elizabeth J. Cartwright, Weiguang Wang, Ludwig Neyses, Angel L. Armesilla

Research output: Contribution to journalArticlepeer-review

Abstract

Cancer is caused by defects in the signalling mechanisms that govern cell proliferation and apoptosis. It is well known that calcium-dependent signalling pathways play a critical role in cell regulation. A tight control of calcium homeostasis by transporters and channel proteins is required to assure a proper functioning of the calcium-sensitive signal transduction pathways that regulate cell growth and apoptosis. The Plasma Membrane Calcium ATPase 2 (PMCA2) has been recently identified as a negative regulator of apoptosis that can play a significant role in cancer progression by conferring cells resistance to apoptosis. We have previously reported an inhibitory interaction between PMCA2 and the calcium-activated signalling molecule calcineurin in breast cancer cells. Here we demonstrate that disruption of the PMCA2/calcineurin interaction in a variety of human breast cancer cells results in activation of the calcineurin/NFAT pathway, up-regulation in the expression of the pro-apoptotic protein Fas Ligand, and in a concomitant loss of cell viability. Reduction in cell viability is the consequence of an increase in cell apoptosis. Impairment of the PMCA2/calcineurin interaction enhances paclitaxel-mediated cytotoxicity of breast tumoral cells. Our results suggest that therapeutic modulation of the PMCA2/calcineurin interaction might have important clinical applications to improve current treatments for breast cancer patients.
Original languageEnglish
Article numberbgs282
Pages (from-to)2362-2368
Number of pages7
JournalCarcinogenesis
Volume33
Issue number12
Early online date7 Sep 2012
DOIs
Publication statusPublished - Dec 2012

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