Orai1 DOWNREGULATION: A MISSING LINK IN UNDERSTANDING

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