ORAI3 silencing alters cell proliferation and promotes mitotic catastrophe and apoptosis in pancreatic adenocarcinoma
ORAI3 silencing alters cell proliferation and promotes mitotic catastrophe and apoptosis in pancreatic adenocarcinoma
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DOI：
10.1016/j.bbamcr.2021.119023
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发表时间：
2021-04-23
影响因子：
5.1
通讯作者：
Prevarskaya, Natalia
中科院分区：
文献类型：
--
作者：
Dubois, Charlotte;Kondratska, Kateryna;Prevarskaya, Natalia
细胞内游离Ca 2+浓度的变化在许多基本的细胞过程中起着核心作用，包括肌肉收缩、神经传递、细胞增殖、分化、基因转录和细胞死亡。已知这些过程中的许多过程由钙库操纵的钙通道（SOC）调节，其中在癌细胞中研究最多的是ORAI 1，使得其他奥赖通道的作用尚未得到充分解决。在这里，我们证明，ORAI3通道在正常（HPDE）和胰腺导管腺癌（PDAC）细胞系中表达，在那里它们形成功能通道，它们的敲除影响钙库操纵的钙内流（SOCE）。更具体地，ORAI3沉默增加PDAC细胞系中的SOCE，而降低正常胰腺细胞系中的SOCE。我们还显示了ORAI3在增殖、细胞周期、活力、有丝分裂灾难和细胞死亡中的作用。最后，我们证明了ORAI3沉默在体内损害胰腺肿瘤生长并诱导细胞死亡，这表明ORAI3可以代表PDAC治疗中的潜在治疗靶点。
Changes in cytosolic free Ca2+ concentration play a central role in many fundamental cellular processes including muscle contraction, neurotransmission, cell proliferation, differentiation, gene transcription and cell death. Many of these processes are known to be regulated by store-operated calcium channels (SOCs), among which ORAI1 is the most studied in cancer cells, leaving the role of other ORAI channels yet inadequately addressed. Here we demonstrate that ORAI3 channels are expressed in both normal (HPDE) and pancreatic ductal adenocarcinoma (PDAC) cell lines, where they form functional channels, their knockdown affecting store operated calcium entry (SOCE). More specifically, ORAI3 silencing increased SOCE in PDAC cell lines, while decreasing SOCE in normal pancreatic cell line. We also show the role of ORAI3 in proliferation, cell cycle, viability, mitotic catastrophe and cell death. Finally, we demonstrate that ORAI3 silencing impairs pancreatic tumor growth and induces cell death in vivo, suggesting that ORAI3 could represent a potential therapeutic target in PDAC treatment.