A novel mechanism underlying phytate‐mediated biological action‐phytate hydrolysates induce intracellular calcium signaling by a Gαq protein‐coupled receptor and phospholipase C‐dependent mechanism in colorectal cancer cells

Phytate (inositol hexa‐phosphate, IP6) possesses multiple biological functions including anticancer activity. IP6 is converted to inositol di‐, tri‐, and tetra‐phosphates (IP2, IP3, and IP4) by phytase in large intestinal microbes; however, their contribution to the IP6‐mediated functions has not been investigated. We have developed the preparations of IP2–4 and IP3‐rich phytate hydrolysate (IP3‐RPH) by IP6 digestion using microbial phytase, and examined the induction of intracellular Ca²⁺ signaling in response to the preparations in colorectal cancer cells. IP2–4, but not inositol (IP0) and IP6, induced increases in intracellular Ca²⁺ concentration (Ca²⁺]_i) in Caco‐2 cells with the following rank order: IP3>IP2=IP4. Inositol tri‐phosphate (IP3)‐RPH induced increases in Ca²⁺]_i in both undifferentiated Caco‐2 and HT‐29 cells, but not in differentiated Caco‐2. The IP3‐RPH‐induced Ca²⁺]_i increase was resistant to extracellular Ca²⁺ depletion, however, it was impaired by inhibitors of phospholipase C, inositol 1, 4, 5 tri‐phosphate receptor, ryanodine receptor, and Gαq protein. These results show that the putative G protein‐coupled receptor on the plasma membrane senses the IP6 hydrolysates and activates phospholipase Cβ, resulting in Ca²⁺ mobilization through Ca²⁺ channels coupled with the inositol 1, 4, 5 tri‐phosphate and ryanodine receptors on the sarco‐endoplasmic reticulum Ca²⁺ store in colorectal cancer cells.