Role of the sodium/calcium exchanger type 3 in cancer cells.

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.