title: Orai1 contributes to the establishment of an apoptosis-resistant phenotype in prostate cancer cells.
abstract: 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.
authors.affiliation: INSERM U1003, Equipe labellisée par la Ligue Nationale contre le cancer, Villeneuve d'Ascq, France.
authors.forename: M
authors.initials: M
authors.lastname: Flourakis
authors.forename: V
authors.initials: V
authors.lastname: Lehen'kyi
authors.forename: B
authors.initials: B
authors.lastname: Beck
authors.forename: M
authors.initials: M
authors.lastname: Raphaël
authors.forename: M
authors.initials: M
authors.lastname: Vandenberghe
authors.forename: F V
authors.initials: FV
authors.lastname: Abeele
authors.forename: M
authors.initials: M
authors.lastname: Roudbaraki
authors.forename: G
authors.initials: G
authors.lastname: Lepage
authors.forename: B
authors.initials: B
authors.lastname: Mauroy
authors.forename: C
authors.initials: C
authors.lastname: Romanin
authors.forename: Y
authors.initials: Y
authors.lastname: Shuba
authors.forename: R
authors.initials: R
authors.lastname: Skryma
authors.forename: N
authors.initials: N
authors.lastname: Prevarskaya
mesh_terms: D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009154:Mutation; D009363:Neoplasm Proteins / Q000378:metabolism; D000071740:ORAI1 Protein; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D000071737:Stromal Interaction Molecule 1; D019284:Thapsigargin / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D015220:Calcium Channels; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D014409:Tumor Necrosis Factor-alpha; D019284:Thapsigargin; D002945:Cisplatin; D002118:Calcium