Bong Alice H L, Robitaille Mélanie, Lin Sichun, McCart-Reed Amy, Milevskiy Michael, Angers Stéphane, Roberts-Thomson Sarah J, Monteith Gregory R
School of Pharmacy, The University of Queensland, Woolloongabba, QLD, Australia.
Donelly Centre, University of Toronto, Toronto, ON, M5S 1A8, Canada.
Cell Death Discov. 2024 Oct 1;10(1):421. doi: 10.1038/s41420-024-02183-0.
The release of Ca ions from endoplasmic reticulum calcium stores is a key event in a variety of cellular processes, including gene transcription, migration and proliferation. This release of Ca often occurs through inositol 1,4,5-triphosphate receptors and the activity of these channels and the levels of stored Ca in the endoplasmic reticulum are important regulators of cell death in cancer cells. A recently identified Ca channel of the endoplasmic reticulum is transmembrane and coiled-coil domains 1 (TMCO1). In this study, we link the overexpression of TMCO1 with prognosis in node-positive basal breast cancer patients. We also identify interacting proteins of TMCO1, which include endoplasmic reticulum-resident proteins involved in Ca regulation and proteins directly involved in nucleocytoplasmic transport. Interacting proteins included nuclear transport proteins and TMCO1 was shown to have both nuclear and endoplasmic reticulum localisation in MDA-MB-231 basal breast cancer cells. These studies also define a role for TMCO1 in the regulation of breast cancer cells in their sensitivity to BCL-2/MCL-1 inhibitors, analogous to the role of inositol 1,4,5-triphosphate receptors in the regulation of cell death pathways activated by these agents.
钙离子从内质网钙库中的释放是多种细胞过程中的关键事件，包括基因转录、迁移和增殖。这种钙离子释放通常通过肌醇1,4,5-三磷酸受体发生，并且这些通道的活性以及内质网中储存的钙离子水平是癌细胞中细胞死亡的重要调节因子。最近发现的一种内质网钙通道是跨膜卷曲螺旋结构域1（TMCO1）。在本研究中，我们将TMCO1的过表达与淋巴结阳性基底样乳腺癌患者的预后联系起来。我们还鉴定了TMCO1的相互作用蛋白，其中包括参与钙调节的内质网驻留蛋白和直接参与核质运输的蛋白。相互作用蛋白包括核转运蛋白，并且在MDA-MB-231基底样乳腺癌细胞中，TMCO1显示出同时定位于细胞核和内质网。这些研究还确定了TMCO1在调节乳腺癌细胞对BCL-2/MCL-1抑制剂的敏感性方面的作用，类似于肌醇1,4,5-三磷酸受体在调节由这些药物激活的细胞死亡途径中的作用。
