Calcium channel signalling and modulation in colorectal cancer

Background Colorectal cancer (CRC) is a huge global problem, being the 3rd most common cancer worldwide. It is caused by an interplay between genetic and chromosomal aberrations as well as dietary and lifestyle factors. Calcium channel receptor signalling is important in a number of cancers, in particular calcium releaseactivated calcium (CRAC) channel signalling and more recently PIEZO1. The hypothesis is that modulating these channels will have physiological effects on cancer growth in CRC. Key Results A novel ORAI1 inhibitor, named JPIII, demonstrated better pharmacokinetic properties than existing CRAC channel inhibitors, and inhibited ORAI1 channel function in both CRC and human umbilical vein endothelial cells (HUVECs). Furthermore, JPIII suppressed cell viability, migration and invasion in both CRC and endothelial cells. ORAI1 channel inhibition inhibited cell viability without causing cell death in HUVECs. JPIII reduced cell viability and clonogenicity of CRCs. Furthermore, JPIII treatment activated autophagy whilst simultaneously inhibiting AKT phosphorylation. In addition, a role for PIEZO1 in CRC tumourigenesis is described for the first time. PIEZO1 channels are functionally expressed, and PIEZO1 siRNA knockdown inhibited CRC viability and resulted in an increase in G2/M cell cycle arrest. The Cancer Genome Atlas (TCGA) transcriptome data revealed that ORAI1 and PIEZO1 are differentially overexpressed in CRC relative to normal colon. However, calcium signalling and ion transport processes on the whole are downregulated in CRC. ORAI1 and PIEZO1 expression does not vary across disease stage or survival outcomes. However, expression of both channels was inversely associated with lymphatic invasion. Both ORAI1 and PIEZO1 expression demonstrated a tumour-specific correlation with one another that was not present in normal colon, and expression associated with IGF2R, postulating a potential oncogenic process for further research. Conclusion This work has demonstrated that both ORAI1 and PIEZO1 are involved in CRC molecular signalling