Clioquinol inhibits cell growth in a SERCA2-dependent manner

Clioquinol has been reported to act as a potential therapy for neurodegenerative diseases and cancer. However, the underlying mechanism is unclear. We have previously reported that clioquinol induces S-phase cell cycle arrest through the elevation of calcium levels in human neurotypic SH-SY5Y cells. In this study, different types of cells were observed to detect if the effect of clioquinol on intracellular calcium levels is cell type-specific. The Cell Counting Kit-8 assay showed that clioquinol exhibited varying degrees of concentration-dependent cytotoxicity in different cell lines, and that the growth inhibition caused by it was not related to cell source or carcinogenesis. In addition, the inhibition of cell growth by clioquinol was positively associated with its effect on intracellular calcium content ([Ca²⁺ ]_i ). Furthermore, the elevation of [Ca²⁺ ]_i induced by clioquinol led to S-phase cell cycle arrest. Similar to our previous studies, the increase in [Ca²⁺ ]_i was attributed to changes in the expression levels of the calcium pump SERCA2. Comparison of expression levels of SERCA2 between cell lines showed that cells with high levels of SERCA2 were more sensitive to clioquinol. In addition, analysis using UALCAN and the Human Protein Atlas also showed that the expression of SERCA2 in the corresponding human tissues was similar to that of the cells tested in this study, suggesting potential in the application of clioquinol in the future. In summary, our results expand the understanding of the molecular mechanism of clioquinol and provide an important strategy for the rational use of clioquinol.