title: Disruption of the interaction between PMCA2 and calcineurin triggers apoptosis and enhances paclitaxel-induced cytotoxicity in breast cancer cells.
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.
authors.affiliation: Molecular Pharmacology Group,  Research Institute in Healthcare Sciences,  Dept. of Pharmacy,  School of Applied Sciences,  University of Wolverhampton, Wolverhampton, WV1 1SB,  UK.
authors.forename: Rhiannon R
authors.initials: RR
authors.lastname: Baggott
authors.forename: Tamer M A
authors.initials: TM
authors.lastname: Mohamed
authors.forename: Delvac
authors.initials: D
authors.lastname: Oceandy
authors.forename: Marylouisa
authors.initials: M
authors.lastname: Holton
authors.forename: Marie Cécile
authors.initials: MC
authors.lastname: Blanc
authors.forename: Sandrine C
authors.initials: SC
authors.lastname: Roux-Soro
authors.forename: Sarah
authors.initials: S
authors.lastname: Brown
authors.forename: James E
authors.initials: JE
authors.lastname: Brown
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Cartwright
authors.forename: Weiguang
authors.initials: W
authors.lastname: Wang
authors.forename: Ludwig
authors.initials: L
authors.lastname: Neyses
authors.forename: Angel L
authors.initials: AL
authors.lastname: Armesilla
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D019703:Calcineurin / Q000502:physiology*; D045744:Cell Line, Tumor; D053222:Fas Ligand Protein / Q000032:analysis; D016158:Genes, p53; D006801:Humans; D050778:NFATC Transcription Factors / Q000502:physiology; D017239:Paclitaxel / Q000494:pharmacology*; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000502:physiology*; D011485:Protein Binding / Q000187:drug effects; D015398:Signal Transduction
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D050778:NFATC Transcription Factors; D019703:Calcineurin; D053499:Plasma Membrane Calcium-Transporting ATPases; C506958:ATP2B2 protein, human; D017239:Paclitaxel