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 journalArticle

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.
LanguageEnglish
Article numberbgs282
Pages2362-2368
Number of pages7
JournalCarcinogenesis
Volume33
Issue number12
Early online date7 Sep 2012
DOIs
Publication statusPublished - Dec 2012

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Plasma Membrane Calcium-Transporting ATPases
Calcineurin
Paclitaxel
Apoptosis
Breast Neoplasms
Calcium Signaling
Cell Survival
Calcium
Apoptosis Regulatory Proteins
Fas Ligand Protein
Signal Transduction
Neoplasms
Breast
Homeostasis
Up-Regulation
Cell Proliferation

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Baggott, R. R., Mohamed, T. M. A., Oceandy, D., Holton, M., Blanc, M. C., Roux-Soro, S. C., ... Armesilla, A. L. (2012). Disruption of the interaction between PMCA2 and calcineurin triggers apoptosis and enhances paclitaxel-induced cytotoxicity in breast cancer cells. Carcinogenesis , 33(12), 2362-2368. [bgs282]. https://doi.org/10.1093/carcin/bgs282
Baggott, Rhiannon R. ; Mohamed, Tamer M.A. ; Oceandy, Delvac ; Holton, Marylouisa ; Blanc, Marie C. ; Roux-Soro, Sandrine C. ; Brown, Sarah ; Brown, James E ; Cartwright, Elizabeth J. ; Wang, Weiguang ; Neyses, Ludwig ; Armesilla, Angel L. / Disruption of the interaction between PMCA2 and calcineurin triggers apoptosis and enhances paclitaxel-induced cytotoxicity in breast cancer cells. In: Carcinogenesis . 2012 ; Vol. 33, No. 12. pp. 2362-2368.
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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.",
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Baggott, RR, Mohamed, TMA, Oceandy, D, Holton, M, Blanc, MC, Roux-Soro, SC, Brown, S, Brown, JE, Cartwright, EJ, Wang, W, Neyses, L & Armesilla, AL 2012, 'Disruption of the interaction between PMCA2 and calcineurin triggers apoptosis and enhances paclitaxel-induced cytotoxicity in breast cancer cells' Carcinogenesis , vol. 33, no. 12, bgs282, pp. 2362-2368. https://doi.org/10.1093/carcin/bgs282

Disruption of the interaction between PMCA2 and calcineurin triggers apoptosis and enhances paclitaxel-induced cytotoxicity in breast cancer cells. / Baggott, Rhiannon R.; Mohamed, Tamer M.A.; Oceandy, Delvac; Holton, Marylouisa; Blanc, Marie C.; Roux-Soro, Sandrine C.; Brown, Sarah; Brown, James E; Cartwright, Elizabeth J.; Wang, Weiguang; Neyses, Ludwig; Armesilla, Angel L.

In: Carcinogenesis , Vol. 33, No. 12, bgs282, 12.2012, p. 2362-2368.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Disruption of the interaction between PMCA2 and calcineurin triggers apoptosis and enhances paclitaxel-induced cytotoxicity in breast cancer cells

AU - Baggott, Rhiannon R.

AU - Mohamed, Tamer M.A.

AU - Oceandy, Delvac

AU - Holton, Marylouisa

AU - Blanc, Marie C.

AU - Roux-Soro, Sandrine C.

AU - Brown, Sarah

AU - Brown, James E

AU - Cartwright, Elizabeth J.

AU - Wang, Weiguang

AU - Neyses, Ludwig

AU - Armesilla, Angel L.

PY - 2012/12

Y1 - 2012/12

N2 - 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.

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