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

• Published in: Cell death & disease Vol. 1; no. 9
• Main Authors: Flourakis, Matthieu, Lehen'Kyi, V'Yacheslav, Beck, Benjamin, Raphael, Maylis, Vandenberghe, Matthieu, van Denabeele, Fabien, Roudbaraki, Morad, Lepage, Gilbert, Mauroy, Brigitte, Romanin, Christophe, Shuba, Yaroslave, Skryma, Roman, Prevarskaya, Natalia
• Format: Journal Article
• Language: English
• Published: Nature Publishing Group 01-09-2010
• Subjects: Cancer; Life Sciences; prostate cancer; apoptosis resistance; Orai channels; store-operated calcium entry
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2010.52

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.