Cargando…
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...
Autores principales: | , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1782197453515128832 |
---|---|
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. |
format | Text |
id | pubmed-3032347 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT flourakism orai1contributestotheestablishmentofanapoptosisresistantphenotypeinprostatecancercells AT lehenkyiv orai1contributestotheestablishmentofanapoptosisresistantphenotypeinprostatecancercells AT beckb orai1contributestotheestablishmentofanapoptosisresistantphenotypeinprostatecancercells AT raphaelm orai1contributestotheestablishmentofanapoptosisresistantphenotypeinprostatecancercells AT vandenberghem orai1contributestotheestablishmentofanapoptosisresistantphenotypeinprostatecancercells AT vandenabeelef orai1contributestotheestablishmentofanapoptosisresistantphenotypeinprostatecancercells AT roudbarakim orai1contributestotheestablishmentofanapoptosisresistantphenotypeinprostatecancercells AT lepageg orai1contributestotheestablishmentofanapoptosisresistantphenotypeinprostatecancercells AT mauroyb orai1contributestotheestablishmentofanapoptosisresistantphenotypeinprostatecancercells AT romaninc orai1contributestotheestablishmentofanapoptosisresistantphenotypeinprostatecancercells AT shubay orai1contributestotheestablishmentofanapoptosisresistantphenotypeinprostatecancercells AT skrymar orai1contributestotheestablishmentofanapoptosisresistantphenotypeinprostatecancercells AT prevarskayan orai1contributestotheestablishmentofanapoptosisresistantphenotypeinprostatecancercells |