Galvankova Kristina, Rezuchova Ingeborg, Klena Ladislav, Grman Marian, Gazova Simova, Liskova Veronika, Kozovska Zuzana, Roller Ladislav, Babula Petr, Krizanova Olga
Institute of Clinical and Translational Research, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.
Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.
Eur J Cell Biol. 2025 Jun;104(2):151493. doi: 10.1016/j.ejcb.2025.151493. Epub 2025 Apr 30.
The sodium/calcium exchanger (NCX) type 1 has been well described in various cancers, but little is known about the other two NCX types (NCX2 and NCX3). In this study, we used the selective blocker of NCX3 - YM-244769 to investigate changes in apoptosis induction, migration, proliferation, intracellular calcium and ATP in four cancer cell lines - DLD1, HeLa, MDA-MB-231 and JIMT1. In all four cell lines we observed a concentration-dependent increase in the number of apoptotic cells, as well as reduced migration and proliferation. Induction of hypoxic conditions did not alter the response of these cells to YM-244769 in any of the above-mentioned parameters. These results indicate the role of NCX3 in cancer cell migration, proliferation and apoptosis, as inhibition of NCX1 by the specific blocker SEA0400 had no significant effect on these parameters. However, we verified the effect of NCX3 inhibition by using CRISPR/Cas9 to generate clones in which the SLC8A3 (NCX3) gene was deleted, and we obtained the same results. In addition, mitochondrial respiration was impaired in the clones with NCX3 knocked-out, suggesting that NCX3 also play a role in bioenergetics. In conclusion, we have clearly shown that NCX3 plays an important anti-apoptotic, pro-migratory and proliferative role in the cancer cells by affecting mitochondrial bioenergetics, thus supporting their survival and fate.
1型钠/钙交换体（NCX）在多种癌症中已有充分描述，但对于其他两种NCX类型（NCX2和NCX3）却知之甚少。在本研究中，我们使用NCX3的选择性阻滞剂YM-244769来研究四种癌细胞系（DLD1、HeLa、MDA-MB-231和JIMT1）中凋亡诱导、迁移、增殖、细胞内钙和ATP的变化。在所有四种细胞系中，我们观察到凋亡细胞数量呈浓度依赖性增加，同时迁移和增殖减少。诱导缺氧条件并未改变这些细胞在上述任何参数方面对YM-244769的反应。这些结果表明NCX3在癌细胞迁移、增殖和凋亡中的作用，因为特异性阻滞剂SEA0400对NCX1的抑制对这些参数没有显著影响。然而，我们通过使用CRISPR/Cas9生成缺失SLC8A3（NCX3）基因的克隆来验证NCX3抑制的效果，并获得了相同的结果。此外，NCX3基因敲除的克隆中线粒体呼吸受损，表明NCX3在生物能量学中也发挥作用。总之，我们清楚地表明，NCX3通过影响线粒体生物能量学在癌细胞中发挥重要的抗凋亡、促迁移和增殖作用，从而支持它们的存活和命运。
