Orai1 contributes to the establishment of an apoptosis-resistant phenotype in prostate cancer cells. - Archive ouverte HAL Access content directly
Journal Articles Cell Death and Disease Year : 2010

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

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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.
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inserm-00520275 , version 1 (22-09-2010)

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Matthieu Flourakis, V'Yacheslav Lehen'Kyi, Benjamin Beck, Maylis Raphael, Matthieu Vandenberghe, et al.. Orai1 contributes to the establishment of an apoptosis-resistant phenotype in prostate cancer cells.: Orai1 in apoptosis resistance of prostate cancer. Cell Death and Disease, 2010, 1 (9), pp.e75. ⟨10.1038/cddis.2010.52⟩. ⟨inserm-00520275⟩

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