Channel complexes involved in remodeling of store-operated channels in colon cancer cells and their reversal by DFMO

Abstract

Store-operated Ca2+ entry (SOCE) is the most important Ca2+ entry pathway in non-excitable cells. Colorectal cancer (CRC) show decreased Ca2+ store content and enhanced SOCE that are associated to remodeling of store-operated channels (SOCs), in addition its correlate with cancer hallmarks. Ca2+ remodeling in CRC may consist of changes in expression of Ca2+ channels and pumps and are associated to interaction among different molecular players: nonselective currents driven by Orai1, Orai3 and TRPC1 channels and Stim1 and Stim2 sensors. Difluoromethylornithine (DFMO), a suicide inhibitor of ornithine decarboxylase (ODC), is a strongly preventor of CRC. We asked whether polyamine depletion could be reverse Ca2+ remodelling interactions in CRC. We found that the principal players in normal mucosa cells in SOCE are Orai1 and Stim2, TRPC1 and Stim1 also are presented in low levels. It seems that all this molecules make week interactions between them. However, store-operated channels in CRC display enhanced dual interactions between TRPC1, Stim1 and Orai1 compared to normal cells. Moreover, DFMO treatment decreases specifically the interaction between TRPC1 and Stim1. These data are consistent with previous results that looked like DFMO treatment in CRC cells, specifically affecting the suppression of TRPC1 and Stim1. These results suggest that polyamines contribute to Ca2+ channel remodelling interactions in CRC and DFMO may prevent CRC by reversing channel remodeling.