Walther-Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, 80336 Munich, Germany.
Immunology, Infection and Pandemic Research IIP, Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 80799 Munich, Germany.
Cells. 2024 Oct 31;13(21):1801. doi: 10.3390/cells13211801.
TRPM7 is a divalent cation-permeable channel that is highly active in cancer cells. The pharmacological inhibitors of TRPM7 have been shown to suppress the proliferation of tumor cells, highlighting TRPM7 as a new anticancer drug target. However, the potential benefit of combining TRPM7 inhibitors with conventional anticancer therapies remains unexplored. Here, we used genome-wide transcriptome profiling of human leukemia HAP1 cells to examine cellular responses caused by the application of NS8593, the potent inhibitor of the TRPM7 channel, in comparison with two independent knockout mutations in the gene introduced by the CRISPR/Cas9 approach. This analysis revealed that regulates the expression levels of several transcripts, including (). Consequently, we examined the axis in several non-hematopoietic cells to show that TRPM7 affects the expression of HER2 protein in a Zn-dependent fashion. Moreover, we found that co-administration of pharmacological inhibitors of HER2 and TRPM7 elicited a synergistic antiproliferative effect on HER2-overexpressing SKBR3 cells but not on HER2-deficient MDA-MB-231 breast cancer cells. Hence, our study proposes a new combinatorial strategy for treating HER2-positive breast cancer cells.
TRPM7 是一种二价阳离子渗透性通道，在癌细胞中高度活跃。TRPM7 的药理学抑制剂已被证明能抑制肿瘤细胞的增殖，这突显了 TRPM7 作为一种新的抗癌药物靶点的潜力。然而，TRPM7 抑制剂与传统抗癌疗法联合应用的潜在益处仍有待探索。在这里，我们使用人类白血病 HAP1 细胞的全基因组转录组谱分析，比较了强效 TRPM7 通道抑制剂 NS8593 的应用与 CRISPR/Cas9 方法引入的 基因的两个独立敲除突变所引起的细胞反应。这项分析表明， 调节了包括 （）在内的几个转录本的表达水平。因此，我们在几种非造血细胞中研究了 轴，以表明 TRPM7 以 Zn 依赖性方式影响 HER2 蛋白的表达。此外，我们发现 HER2 和 TRPM7 的药理学抑制剂联合给药对过表达 HER2 的 SKBR3 细胞产生协同的抗增殖作用，但对 HER2 缺失的 MDA-MB-231 乳腺癌细胞没有作用。因此，我们的研究提出了一种治疗 HER2 阳性乳腺癌细胞的新组合策略。
