Pathak Trayambak, Benson J Cory, Johnson Martin T, Xin Ping, Abdelnaby Ahmed Emam, Walter Vonn, Koltun Walter A, Yochum Gregory S, Hempel Nadine, Trebak Mohamed
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Sci Signal. 2025 Jun 24;18(892):eads6550. doi: 10.1126/scisignal.ads6550.
The large amounts of calcium (Ca) stored in the endoplasmic reticulum (ER) and the controlled release of this Ca store into the cytosol regulate many cellular functions, and altered ER Ca homeostasis induces ER stress. Stromal-interacting molecules 1 and 2 (STIM1/2) are homologous ER-resident Ca sensors that synergistically activate cytosolic Ca influx through Orai channels to promote Ca-dependent changes in gene expression and ER Ca refilling. Here, we demonstrated that reduced abundance of STIM2, but not that of STIM1, was associated with poor prognosis in colorectal cancer (CRC). STIM2-deficient CRC cells showed enhanced ER Ca content in a manner dependent on the ER Ca pump SERCA2, increased expression of genes associated with protein translation, and transcriptional and metabolic rewiring. STIM2 deficiency in CRC xenografts led to increased tumor size, invasion, and metastasis. STIM2 loss activated the expression of genes involved in ER stress responses in a manner dependent on the chaperone BiP and the transcription factor ATF4 and independent of Orai channels. These results suggest that loss of STIM2 may inform CRC prognosis.
内质网（ER）中储存的大量钙（Ca）以及该钙库向细胞质的可控释放调节着许多细胞功能，而内质网钙稳态的改变会引发内质网应激。基质相互作用分子1和2（STIM1/2）是内质网驻留的同源钙传感器，它们通过Orai通道协同激活细胞质钙内流，以促进基因表达中依赖钙的变化以及内质网钙再填充。在此，我们证明，结直肠癌（CRC）患者预后不良与STIM2丰度降低有关，而与STIM1丰度降低无关。STIM2缺陷的结直肠癌细胞以依赖内质网钙泵SERCA2的方式表现出内质网钙含量增加、与蛋白质翻译相关基因的表达增加以及转录和代谢重编程。结直肠癌异种移植模型中STIM2缺陷导致肿瘤大小增加、侵袭和转移。STIM2缺失以依赖伴侣蛋白BiP和转录因子ATF4且独立于Orai通道的方式激活内质网应激反应相关基因的表达。这些结果表明，STIM2缺失可能为结直肠癌的预后提供信息。
