Identification of TRPM7-dependent pathways

Previous research has indicated that the plasma membrane channel kinase Transient Receptor Potential Cation Channel Subfamily M Member 7 (TRPM7) is involved in the uptake of divalent cations, including Zn2+, Mg2+, and Ca2+ [3-7], which are required for many cellular processes. Studies with cultured cells and animal disease models demonstrated that inactivation of TRPM7 led to impaired proliferation of cancer cells. However, mechanistically, the role of TRPM7 in tumour progression remains poorly understood. In our study, we conducted electrophysiological and cell biological experiments to investigate how intracellular Mg2+ interacts directly with TRPM7, leading to the inhibition of TRPM7 currents. In addition, we used genome-wide transcriptome profiling of haploid human leukemia (HAP1) cells to identify cellular pathways altered upon introduction of loss-of-function mutations in the TRPM7 gene using the CRISPR/Cas9 approach or the administration of a pharmacological inhibitor of the TRPM7 channels, NS8593. Notably, among the affected gene networks, we observed that the expression levels of human epidermal growth factor receptor HER2 (ERRB2), a well-known oncogene in breast cancer, were altered upon TRPM7 inhibition. Consequently, we examined the interplay of TRPM7 and HER2 in several cell lines and found that TRPM7 mediates Zn2+-dependent downregulation of HER2 protein levels. In addition, we observed that simultaneous administration of CP724714 (an inhibitor of HER2) and NS8593 (a TRPM7 inhibitor) synergistically suppressed the proliferation of HER2-positive SKBR3 cells but not HER2-negative MDA-MB-231 cells. Our study, therefore, provides new insights into the regulatory mechanisms of the TRPM7 channel and uncovers new cellular counterparts of TRPM7. We demonstrate that the inhibition of TRPM7, in combination with HER2-targeted therapy, can more effectively suppress the proliferation of HER2-positive breast cancer cells.