前列腺癌（PCa）是全球最常见的男性诊断癌症之一。由于例行筛查测试和可用治疗的效果，过去几十年中PCa相关的死亡人数显著减少。然而，如果在晚期检测到PCa，即癌细胞已经从原发肿瘤脱落并扩散和侵袭其他部位时，PCa仍然是一个重大威胁。钙（Ca2+）信道及其蛋白质调节因子现在被视为癌症的标志物，其中一些已在PCa中得到很好的研究。在这些Ca2+通道中，ORAI通道家族的3号同型体已被证明通过花生四烯酸介导的Ca2+进入来调节PCa细胞的增殖，需要STIM1（基质相互作用分子1）的参与。然而，目前还没有研究证明“被忽视”的STIM2同型体在PCa中的作用，或者它是否可能与ORAI3相互作用以促进肿瘤性行为。在本研究中，我们证明ORAI3和STIM2在人类PCa组织中上调。在老年KIMAP（敲入小鼠前列腺腺癌）小鼠中，ORAI3和STIM2 mRNA水平明显高于ORAI1和STIM1。在体外实验中，我们表明ORAI3和STIM2在PC-3细胞的基础条件下相互作用。ORAI3沉默增加了储存激活的Ca2+进入（SOCE），并显著增加了细胞周期G2/M期的细胞群体，与ORAI3作为SOCE的负调节因子的作用一致。检测到更高水平的CDK1-Y15/Cyclin B1，并在ORAI3沉默后出现了有丝分裂阻滞相关的细胞死亡，导致Bax/Bcl-2介导的凋亡途径和caspase-8的激活和剪切。M期中STIM2和ORAI3的表达增加，而STIM1的表达和SOCE幅度明显降低。综上所述，ORAI3-STIM2复合物通过逃避有丝分裂灾难使PCa细胞成功进行有丝分裂。版权所有©2023 Elsevier Ltd.保留所有权利。

Prostate cancer (PCa) represents one of the most frequent diagnosed cancer in males worldwide. Due to routine screening tests and the efficiency of available treatments, PCa-related deaths have significantly decreased over the past decades. However, PCa remains a critical threat if detected at a late stage in which, cancer cells would have already detached from the primary tumor to spread and invade other parts of the body. Calcium (Ca2+) channels and their protein regulators are now considered as hallmarks of cancer and some of them have been well examined in PCa. Among these Ca2+ channels, isoform 3 of the ORAI channel family has been shown to regulate the proliferation of PCa cells via the Arachidonic Acid-mediated Ca2+ entry, requiring the involvement of STIM1 (Stromal Interaction Molecule 1). Still, no study has yet demonstrated a role of the "neglected" STIM2 isoform in PCa or if it may interact with ORAI3 to promote an oncogenic behavior. In this study, we demonstrate that ORAI3 and STIM2 are upregulated in human PCa tissues. In old KIMAP (Knock-In Mouse Prostate Adenocarcinoma) mice, ORAI3 and STIM2 mRNA levels were significantly higher than ORAI1 and STIM1. In vitro, we show that ORAI3-STIM2 interact under basal conditions in PC-3 cells. ORAI3 silencing increased Store Operated Ca2+ Entry (SOCE) and induced a significant increase of the cell population in G2/M phase of the cell cycle, consistent with the role of ORAI3 as a negative regulator of SOCE. Higher expression levels of CDK1-Y15/Cyclin B1 were detected and mitotic arrest-related death occurred after ORAI3 silencing, which resulted in activating Bax/Bcl-2-mediated apoptotic pathway and caspase-8 activation and cleavage. STIM2 and ORAI3 expression increased in M phase while STIM1 expression and SOCE amplitude significantly decreased. Taken together, ORAI3 -STIM2 complex allows a successful progression through mitosis of PCa cells by evading mitotic catastrophe.Copyright © 2023 Elsevier Ltd. All rights reserved.