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

• Published in: Cell death & disease Vol. 1; no. 9; p. e75
• Main Authors: Flourakis, M, Lehen'kyi, V, Beck, B, Raphaël, M, Vandenberghe, M, Abeele, F V, Roudbaraki, M, Lepage, G, Mauroy, B, Romanin, C, Shuba, Y, Skryma, R, Prevarskaya, N
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2010; Springer Nature B.V; Nature Publishing Group
• Subjects: 631/45/269/1146; 631/80/304; 631/80/82/23; 692/699/67/589/466; Amino Acid Substitution; Antibodies; Antineoplastic Agents - therapeutic use; Apoptosis; Biochemistry; Biomedical and Life Sciences; Calcium - metabolism; Calcium Channels - genetics; Calcium Channels - metabolism; Calcium Channels - physiology; Cell Biology; Cell Culture; Cell Line, Tumor; Cisplatin - therapeutic use; Humans; Immunology; Life Sciences; Male; Membrane Proteins - metabolism; Mutation; Neoplasm Proteins - metabolism; ORAI1 Protein; Original; original-article; Phenotype; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Stromal Interaction Molecule 1; Thapsigargin - therapeutic use; Tumor Necrosis Factor-alpha - therapeutic use; prostate cancer; apoptosis resistance; Orai channels; store-operated calcium entry
• DOI: 10.1038/cddis.2010.52
• ISSN: 2041-4889

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.