Differential Redox Regulation of Ca2+ Signaling and Viability in Normal and Malignant Prostate Cells
Differential Redox Regulation of Ca2+ Signaling and Viability in Normal and Malignant Prostate Cells
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DOI：
10.1016/j.bpj.2015.08.006
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发表时间：
2015-10-06
影响因子：
3.4
通讯作者：
Peinelt, Christine
中科院分区：
文献类型：
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作者：
Holzmann, Christian;Kilch, Tatiana;Peinelt, Christine
在前列腺癌中，活性氧物种(ROS)升高，钙信号转导受损。因此，一些新的治疗策略已经被开发出来，以靶向前列腺癌中改变的ROS和钙信号通路。在这里，我们研究了来自健康组织和前列腺癌细胞系(LNCaP、DU145和PC3)的原代人前列腺上皮细胞(HPECs)中ROS引起的细胞内钙离子的变化和对细胞活力的抑制。在hPECs中，LNCaP和DU145 H_2O_2诱导最初的Ca~(2+)增加，而在前列腺癌细胞中，这种增加被高浓度H_2O_2所阻断。当细胞内钙离子储存耗尽时，储存操作的钙离子进入(SOCE)被激活。SOCE通道可以由六面体轨道通道形成；然而，轨道可以与其同系物Orai3形成异多聚体。由于Orai3缺乏氧化还原感受器RAIL(Cys-195)，T细胞中Orai1/Orai3的比例决定了SOCE的氧化还原敏感性和细胞活力。在前列腺癌细胞中，与hPECs相比，SOCE在较低浓度的过氧化氢中被阻断。对hPECs、LNCaP、DU145和PC3的数据以及先前发表的来自幼稚T-H细胞和效应T-H细胞的数据的分析表明，Orai1/Orai3比率与SOCE氧化还原敏感性和细胞存活率之间存在强烈的相关性。因此，我们的数据支持这一概念，即hPEC和前列腺癌细胞中的钙离子通道是异构体Orai1/Orai3通道，在前列腺癌肿瘤细胞中Orai1/Orai3比率增加。此外，ROS诱导的前列腺癌细胞内钙信号的改变可能有助于这些细胞对ROS的更高敏感性。
In prostate cancer, reactive oxygen species (ROS) are elevated and Ca2+ signaling is impaired. Thus, several novel therapeutic strategies have been developed to target altered ROS and Ca2+ signaling pathways in prostate cancer. Here, we investigate alterations of intracellular Ca2+ and inhibition of cell viability caused by ROS in primary human prostate epithelial cells (hPECs) from healthy tissue and prostate cancer cell lines (LNCaP, DU145, and PC3). In hPECs, LNCaP and DU145 H2O2 induces an initial Ca2+ increase, which in prostate cancer cells is blocked at high concentrations of H2O2. Upon depletion of intracellular Ca2+ stores, store-operated Ca2+ entry (SOCE) is activated. SOCE channels can be formed by hexameric rail channels; however, rail can form heteromultimers with its homolog, Orai3. Since the redox sensor of rail (Cys-195) is absent in Orai3, the Orai1/Orai3 ratio in T cells determines the redox sensitivity of SOCE and cell viability. In prostate cancer cells, SOCE is blocked at lower concentrations of H2O2 compared with hPECs. An analysis of data from hPECs, LNCaP, DU145, and PC3, as well as previously published data from naive and effector T-H cells, demonstrates a strong correlation between the Orai1/Orai3 ratio and the SOCE redox sensitivity and cell viability. Therefore, our data support the concept that store-operated Ca2+ channels in hPECs and prostate cancer cells are heteromeric Orai1/Orai3 channels with an increased Orai1/Orai3 ratio in cells derived from prostate cancer tumors. In addition, ROS-induced alterations in Ca2+ signaling in prostate cancer cells may contribute to the higher sensitivity of these cells to ROS.