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Orai1 contributes to the establishment of an apoptosis-resistant phenotype in prostate cancer cells

The molecular nature of calcium (Ca(2+))-dependent mechanisms and the ion channels having a major role in the apoptosis of cancer cells remain a subject of debate. Here, we show that the recently identified Orai1 protein represents the major molecular component of endogenous store-operated Ca(2+) en...

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Autores principales: Flourakis, M, Lehen'kyi, V, Beck, B, Raphaël, M, Vandenberghe, M, Vanden Abeele, F, Roudbaraki, M, Lepage, G, Mauroy, B, Romanin, C, Shuba, Y, Skryma, R, Prevarskaya, N
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3032347/
https://www.ncbi.nlm.nih.gov/pubmed/21364678
http://dx.doi.org/10.1038/cddis.2010.52
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author Flourakis, M
Lehen'kyi, V
Beck, B
Raphaël, M
Vandenberghe, M
Vanden Abeele, F
Roudbaraki, M
Lepage, G
Mauroy, B
Romanin, C
Shuba, Y
Skryma, R
Prevarskaya, N
author_facet Flourakis, M
Lehen'kyi, V
Beck, B
Raphaël, M
Vandenberghe, M
Vanden Abeele, F
Roudbaraki, M
Lepage, G
Mauroy, B
Romanin, C
Shuba, Y
Skryma, R
Prevarskaya, N
author_sort Flourakis, M
collection PubMed
description The molecular nature of calcium (Ca(2+))-dependent mechanisms and the ion channels having a major role in the apoptosis of cancer cells remain a subject of debate. Here, we show that the recently identified Orai1 protein represents the major molecular component of endogenous store-operated Ca(2+) entry (SOCE) in human prostate cancer (PCa) cells, and constitutes the principal source of Ca(2+) influx used by the cell to trigger apoptosis. The downregulation of Orai1, and consequently SOCE, protects the cells from diverse apoptosis-inducing pathways, such as those induced by thapsigargin (Tg), tumor necrosis factor α, and cisplatin/oxaliplatin. The transfection of functional Orai1 mutants, such as R91W, a selectivity mutant, and L273S, a coiled-coil mutant, into the cells significantly decreased both SOCE and the rate of Tg-induced apoptosis. This suggests that the functional coupling of STIM1 to Orai1, as well as Orai1 Ca(2+)-selectivity as a channel, is required for its pro-apoptotic effects. We have also shown that the apoptosis resistance of androgen-independent PCa cells is associated with the downregulation of Orai1 expression as well as SOCE. Orai1 rescue, following Orai1 transfection of steroid-deprived cells, re-established the store-operated channel current and restored the normal rate of apoptosis. Thus, Orai1 has a pivotal role in the triggering of apoptosis, irrespective of apoptosis-inducing stimuli, and in the establishment of an apoptosis-resistant phenotype in PCa cells.
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spelling pubmed-30323472011-02-24 Orai1 contributes to the establishment of an apoptosis-resistant phenotype in prostate cancer cells Flourakis, M Lehen'kyi, V Beck, B Raphaël, M Vandenberghe, M Vanden Abeele, F Roudbaraki, M Lepage, G Mauroy, B Romanin, C Shuba, Y Skryma, R Prevarskaya, N Cell Death Dis Original Article The molecular nature of calcium (Ca(2+))-dependent mechanisms and the ion channels having a major role in the apoptosis of cancer cells remain a subject of debate. Here, we show that the recently identified Orai1 protein represents the major molecular component of endogenous store-operated Ca(2+) entry (SOCE) in human prostate cancer (PCa) cells, and constitutes the principal source of Ca(2+) influx used by the cell to trigger apoptosis. The downregulation of Orai1, and consequently SOCE, protects the cells from diverse apoptosis-inducing pathways, such as those induced by thapsigargin (Tg), tumor necrosis factor α, and cisplatin/oxaliplatin. The transfection of functional Orai1 mutants, such as R91W, a selectivity mutant, and L273S, a coiled-coil mutant, into the cells significantly decreased both SOCE and the rate of Tg-induced apoptosis. This suggests that the functional coupling of STIM1 to Orai1, as well as Orai1 Ca(2+)-selectivity as a channel, is required for its pro-apoptotic effects. We have also shown that the apoptosis resistance of androgen-independent PCa cells is associated with the downregulation of Orai1 expression as well as SOCE. Orai1 rescue, following Orai1 transfection of steroid-deprived cells, re-established the store-operated channel current and restored the normal rate of apoptosis. Thus, Orai1 has a pivotal role in the triggering of apoptosis, irrespective of apoptosis-inducing stimuli, and in the establishment of an apoptosis-resistant phenotype in PCa cells. Nature Publishing Group 2010-09 2010-09-16 /pmc/articles/PMC3032347/ /pubmed/21364678 http://dx.doi.org/10.1038/cddis.2010.52 Text en Copyright © 2010 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
spellingShingle Original Article
Flourakis, M
Lehen'kyi, V
Beck, B
Raphaël, M
Vandenberghe, M
Vanden Abeele, F
Roudbaraki, M
Lepage, G
Mauroy, B
Romanin, C
Shuba, Y
Skryma, R
Prevarskaya, N
Orai1 contributes to the establishment of an apoptosis-resistant phenotype in prostate cancer cells
title Orai1 contributes to the establishment of an apoptosis-resistant phenotype in prostate cancer cells
title_full Orai1 contributes to the establishment of an apoptosis-resistant phenotype in prostate cancer cells
title_fullStr Orai1 contributes to the establishment of an apoptosis-resistant phenotype in prostate cancer cells
title_full_unstemmed Orai1 contributes to the establishment of an apoptosis-resistant phenotype in prostate cancer cells
title_short Orai1 contributes to the establishment of an apoptosis-resistant phenotype in prostate cancer cells
title_sort orai1 contributes to the establishment of an apoptosis-resistant phenotype in prostate cancer cells
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3032347/
https://www.ncbi.nlm.nih.gov/pubmed/21364678
http://dx.doi.org/10.1038/cddis.2010.52
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