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

Authors
  • Baggott, Rhiannon R
  • Mohamed, Tamer M A
  • Oceandy, Delvac
  • Holton, Marylouisa
  • Blanc, Marie Cécile
  • Roux-Soro, Sandrine C
  • Brown, Sarah
  • Brown, James E
  • Cartwright, Elizabeth J
  • Wang, Weiguang
  • Neyses, Ludwig
  • Armesilla, Angel L
Type
Published Article
Journal
Carcinogenesis
Publisher
Oxford University Press
Publication Date
Dec 01, 2012
Volume
33
Issue
12
Pages
2362–2368
Identifiers
DOI: 10.1093/carcin/bgs282
PMID: 22962307
Source
Medline
License
Unknown

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, upregulation 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.

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