10th ECS Meeting, Leuven, Sept. 17-20, 2008 – POSTER C-22 Orai1 DOWNREGULATION: A MISSING LINK IN UNDERSTANDING THE PROSTATE CANCER APOPTOSIS RESISTANCE FLOURAKIS M., BECK B., LEHEN’KYI V., GKIKA D., ROUDBARAKI M., SKRYMA R. & PREVARSKAYA N. Inserm, U-800, Equipe labellisée par la Ligue Nationale contre le cancer, and Université des Sciences et Technologies de Lille (USTL), F-59655 Villeneuve d’Ascq, France. Prostate cancer (PCa) is one of the leading threats to men’s health. During the early stage, when it depends on androgens for growth and survival, androgen ablation therapy may be effective in causing tumors to regress, while, in the later, androgen-independent, stage there is currently no successful therapy. The progression to androgen independence is associated with the appearance of new cell phenotypes, characterized by a low apoptosis rate. It is, therefore, vital to understand what drives PCa to apoptosis resistance. We have previously shown that apoptosis inhibition in androgen-independent PCa cells is associated with the downregulation of Store Operated Calcium Entry (SOCE), due to the decrease in the number of functional channels activated following endoplasmic reticulum calcium store depletion. However, the molecular nature of these channels, which play a major role in PCa cell apoptosis induction, has not yet been elucidated. Here, we show that the recently-identified Orai1/CRACM1 protein is a store-operated calcium channel in androgen-dependent human prostate cancer (LNCaP) cells. The expression of Orai1/CRACM1 and the amplitude of store-operated current decreased dramatically in androgen-deprived cells. This downregulation of the Orai1/CRACM1 channels leads to the inhibition of sustained SOCE and, subsequently, to the decrease in apoptosis. Orai1/CRACM1 knockdown protects LNCaP cells from thapsigargin-induced apoptosis. Thus, our work demonstrates that Orai1/CRACM1 plays a pivotal role in prostate cancer progression to an apoptosis-resistant phenotype. Consequently, it is a potentially attractive target for therapeutic intervention. Furthermore, this study is the first to show the role of Orai1/CRACM1 in physiopathology outside the immune system. Keywords: store-operated Ca2+ entry, apoptosis, prostate cancer, Orai1