Sanchez-Collado Jose, Lopez Jose J, Cantonero Carlos, Jardin Isaac, Regodón Sergio, Redondo Pedro C, Gordillo Juan, Smani Tarik, Salido Gines M, Rosado Juan A
Cellular Physiology Research Group, Department of Physiology, Institute of Molecular Pathology Biomarkers (IMPB), University of Extremadura, 10003 Caceres, Spain.
Pathology Service, Hospital de Merida, 06800 Merida, Spain.
Cancers (Basel). 2021 Dec 27;14(1):114. doi: 10.3390/cancers14010114.
Breast cancer is a heterogeneous disease from the histological and molecular expression point of view, and this heterogeneity determines cancer aggressiveness. Store-operated Ca entry (SOCE), a major mechanism for Ca entry in non-excitable cells, is significantly remodeled in cancer cells and plays an important role in the development and support of different cancer hallmarks. The store-operated CRAC (Ca release-activated Ca) channels are predominantly comprised of Orai1 but the participation of Orai2 and Orai3 subunits has been reported to modulate the magnitude of Ca responses. Here we provide evidence for a heterogeneous expression of Orai2 among different breast cancer cell lines. In the HER2 and triple negative breast cancer cell lines SKBR3 and BT20, respectively, where the expression of Orai2 was greater, Orai2 modulates the magnitude of SOCE and sustain Ca oscillations in response to carbachol. Interestingly, in these cells Orai2 modulates the activation of NFAT1 and NFAT4 in response to high and low agonist concentrations. Finally, we have found that, in cells with high Orai2 expression, Orai2 knockdown leads to cell cycle arrest at the G0-G1 phase and decreases apoptosis resistance upon cisplatin treatment. Altogether, these findings indicate that, in breast cancer cells with a high Orai2 expression, Orai2 plays a relevant functional role in agonist-evoked Ca signals, cell proliferation and apoptosis resistance.
从组织学和分子表达的角度来看，乳腺癌是一种异质性疾病，这种异质性决定了癌症的侵袭性。储存性钙内流（SOCE）是非兴奋性细胞中钙内流的主要机制，在癌细胞中显著重塑，并在不同癌症特征的发展和维持中发挥重要作用。储存性钙释放激活钙（CRAC）通道主要由Orai1组成，但据报道Orai2和Orai3亚基的参与会调节钙反应的幅度。在这里，我们提供了不同乳腺癌细胞系中Orai2异质性表达的证据。在HER2和三阴性乳腺癌细胞系SKBR3和BT20中，Orai2的表达分别更高，Orai2调节SOCE的幅度，并在对卡巴胆碱的反应中维持钙振荡。有趣的是，在这些细胞中，Orai2在高浓度和低浓度激动剂的作用下调节NFAT1和NFAT4的激活。最后，我们发现，在Orai2高表达的细胞中，敲低Orai2会导致细胞周期停滞在G0-G1期，并降低顺铂处理后的抗凋亡能力。总之，这些发现表明，在Orai2高表达的乳腺癌细胞中，Orai2在激动剂诱发的钙信号、细胞增殖和抗凋亡中发挥着相关的功能作用。
