Redondo Pedro C, Lopez Jose J, Alvarado Sandra, Jardin Isaac, Nieto-Felipe Joel, Macias-Diaz Alvaro, Jimenez-Velarde Vanesa, Salido Gines M, Rosado Juan A
Department of Physiology, Institute of Molecular Pathology Biomarkers, University of Extremadura, 10003 Caceres, Spain.
Cancers (Basel). 2024 Jul 11;16(14):2518. doi: 10.3390/cancers16142518.
Extended synaptotagmins (E-Syts) are endoplasmic reticulum (ER)-associated proteins that facilitate the tethering of the ER to the plasma membrane (PM), participating in lipid transfer between the membranes and supporting the Orai1-STIM1 interaction at ER-PM junctions. Orai1 and STIM1 are the core proteins of store-operated Ca entry (SOCE), a major mechanism for Ca influx that regulates a variety of cellular functions. Aberrant modulation of SOCE in cells from different types of cancer has been reported to underlie the development of several tumoral features. Here we show that estrogen receptor-positive (ER+) breast cancer MCF7 and T47D cells and triple-negative breast cancer (TNBC) MDA-MB-231 cells overexpress E-Syt1 and E-Syt2 at the protein level; the latter is also overexpressed in the TNBC BT20 cell line. E-Syt1 and E-Syt2 knockdown was without effect on SOCE in non-tumoral MCF10A breast epithelial cells and ER+ T47D breast cancer cells; however, SOCE was significantly attenuated in ER+ MCF7 cells and TNBC MDA-MB-231 and BT20 cells upon transfection with siRNA E-Syt1 or E-Syt2. Consistent with this, E-Syt1 and E-Syt2 knockdown significantly reduced cell migration and viability in ER+ MCF7 cells and the TNBC cells investigated. To summarize, E-Syt1 and E-Syt2 play a relevant functional role in breast cancer cells.
延伸突触结合蛋白（E-Syts）是与内质网（ER）相关的蛋白质，可促进内质网与质膜（PM）的栓系，参与膜间脂质转移，并支持内质网-质膜连接处的Orai1-STIM1相互作用。Orai1和STIM1是储存性钙内流（SOCE）的核心蛋白，SOCE是钙内流的主要机制，可调节多种细胞功能。据报道，不同类型癌症细胞中SOCE的异常调节是几种肿瘤特征发展的基础。在此，我们表明雌激素受体阳性（ER+）乳腺癌MCF7和T47D细胞以及三阴性乳腺癌（TNBC）MDA-MB-231细胞在蛋白质水平上过表达E-Syt1和E-Syt2；后者在TNBC BT20细胞系中也过表达。E-Syt1和E-Syt2基因敲低对非肿瘤性MCF10A乳腺上皮细胞和ER+ T47D乳腺癌细胞中的SOCE没有影响；然而，在用siRNA E-Syt1或E-Syt2转染后，ER+ MCF7细胞以及TNBC MDA-MB-231和BT20细胞中的SOCE显著减弱。与此一致的是，E-Syt1和E-Syt2基因敲低显著降低了ER+ MCF7细胞和所研究的TNBC细胞的迁移和活力。总之，E-Syt1和E-Syt2在乳腺癌细胞中发挥相关的功能作用。
