FIGURE 15.

Hypothesis of molecular basis of Ca²⁺ remodeling in colon cancer. The “Ca²⁺ signature” of colon carcinoma cells is enhanced SOCE, differential SOCs, and depleted Ca²⁺ stores. This remodeling is associated with increased protein expression of TRPC1, STIM1, ORAI1, ORAI2, and ORAI3 in tumor cells along with loss of STIM2 protein. Normal cells show small SOCE mediated by canonical I_CRAC carried by ORAI1. STIM2 protein in normal cells may limit STIM1/ORAI1 interaction and may signal for large Ca²⁺ store content, thus preventing SOCE activation and TRPC1 functional expression. In this scenario, cell proliferation and migration are limited, and cells are prone to die as Ca²⁺ stores are loaded. Loss of STIM2 renders cells under control of STIM1 that set Ca²⁺ store content to a lower level. Like in Darier disease, depletion of Ca²⁺ stores likely promotes TRPC1 functional expression. In addition, loss of STIM2 may also favor interaction of STIM1 with ORAI1 and TRPC1 resulting in enhanced I_CRAC and the appearance of a nonselective current.