[Possible involvement of inositol 1, 4, 5-trisphosphate receptor type 3 (IP3R3) in the peritoneal dissemination of gastric cancers].

Our previous study using a cDNA microarray demonstrated that positive identification of differently expressed genes among gastric cancer cells involved in peritoneal dissemination could be accomplished. One of these genes with overexpression is inositol 1, 4, 5-trisphosphate receptor type 3 (IP3R3). IP3R3 is an intracellular Ca2+ release channel responsible for mobilizing stored Ca2+. Three different receptor types have been molecularly cloned, and their genes have been classified into a family. But the role of the IP3 signaling pathway in the peritoneal dissemination of gastric cancers is still unclear. In this study, IP3R3 is overexpressed in gastric cancer cell lines established from malignant ascites, but weakly expressed in gastric cancer cell lines established from primary tumor as well as in normal gastric epithelial cells. IP3R1 and 2 are expressed only weakly or not at all in these cells. The antagonist of IP3R, 2-APB, inhibited cell proliferation and induced apoptosis of gastric cancer cells from malignant ascites at concentrations of 100 nM to 100 microM in a dose dependent manner. Conversely, 2-APB showed a weak effect on other gastric cancer cells established from primary tumors (SNU1), lymph node metastases or liver metastases (MKN1 or 74), methothelial cell lines Met5A and myeloid leukemia cell HL60 cells. This suggests that this inhibitory effect depends on the level of IP3R3 expression. As cells that express IP3R3 mRNA (i.e., pancreatic aciner cells) are known to have a secretory function in which IP3/Ca2+ signaling has been shown to be involved, IP3R3 may be a prerequisite for secretion in gastric cancer cells. These results indicate that IP3R3 may be specifically involved in gastric cancer peritoneal dissemination and that IP3R3 may be a molecular target of the peritoneal dissemination of gastric cancer. Its antagonist, 2-APB, may thus be useful for the treatment of gastric cancer, especially for peritoneal dissemination.