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Carboxyamidotriazole-induced inhibition of mitochondrial calcium import blocks capacitative calcium entry and cell proliferation in HEK-293 cells

Carboxyamidotriazole-induced inhibition of mitochondrial calcium import blocks capacitative calcium entry and cell proliferation in HEK-293 cells. Mignen, Olivier; Brink, Christine; Enfissi, Antoine; Nadkarni, Aditi; Shuttleworth, Trevor J.; Giovannucci, David R.; Capiod, Thierry ( Department of Pharmacology and Physiology, University of Rochester, Rochester, NY 14642, USA). Journal of Cell Science, 118(23), 5615-5623 (English) 2005 Company of Biologists Ltd. CODEN: JNCSAI. ISSN: 0021-9533. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Blocking calcium entry may prevent normal and pathol. cell proliferation. There is evidence suggesting that mols. such as carboxyamidotriazole, widely used in anti-cancer therapy based on its ability to block calcium entry in nonexcitable cells, also have antiproliferative properties. We found that carboxyamidotriazole and the capacitative calcium entry blocker 2-aminoethoxydiphenyl borate inhibited proliferation in HEK-293 cells with IC50 values of 1.6 and 50 mM, resp. Capacitative calcium entry is activated as a result of intracellular calcium store depletion. However, non-capacitative calcium entry pathways exist that are independent of store depletion and are activated by arachidonic acid and diacylglycerol, generated subsequent to G protein coupled receptor stimulation. 524-95-8 and 7440-70-2 which are cas registry numbers of substances are two of reagents here. We found that carboxyamidotriazole completely inhibited the capacitative calcium entry and had no effect on the amplitude of arachidonic-acid-activated non-capacitative calcium entry. However, investigation of the effects of carboxyamidotriazole on mitochondrial calcium dynamics induced by carbachol, capacitative calcium entry and exogenously set calcium loads in intact and digitonin-permeabilized cells revealed that carboxyamidotriazole inhibited both calcium entry and mitochondrial calcium uptake in a time-dependent manner. Mitochondrial inner-membrane potential was altered by carboxyamidotriazole treatment, suggesting that carboxyamidotriazole antagonizes mitochondrial calcium import and thus local calcium clearance, which is crucial for the maintenance of capacitative calcium entry. .

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

Possible involvement of inositol 1,4,5-trisphosphate receptor type 3 (IP3R3) in the peritoneal dissemination of gastric cancers. Sakakura, Chouhei; Hagiwara, Akeo; Fukuda, Kenichiro; Shimomura, Katsumi; Takagi, Tsuyoshi; Kin, Shuichi; Nakase, Yuenn; Fujiyama, Junshin; Mikoshiba, Katsuhiko; Okazaki, Yasushi; Yamagishi, Hisakazu (Department of Digestive Surgery, Department of Hygiene, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kawaramachi-dori, Kyoto 602-8566, Japan). Anticancer Research, 23(5A), 3691-3697 (English) 2003 International Institute of Anticancer Research. CODEN: ANTRD4. ISSN: 0250-7005. DOCUMENT TYPE: Journal CA Section: 14 (Mammalian Pathological Biochemistry) Section cross-reference(s): 1 Our previous study using cDNA microarray showed that differentially expressed genes among gastric cancer cells involved in peritoneal dissemination could be pos. identified. One of these genes, which is overexpressed, is inositol 1,4,5-trisphosphate receptor type 3 (IP3R3). IP3R3 is responsible for the intracellular Ca2+ release channel and for mobilizing stored Ca2+. Three different receptor types have been molecularly cloned and their genes have been classified into a family. However, the role of the IP3 signaling pathway in the peritoneal dissemination of gastric cancer is still unclear. In the study presented here, the IP3R3 is showed to be overexpressed in gastric cancer cell lines established from malignant ascites, but weakly expressed in a gastric cancer cell line established from primary tumor as well as normal gastric epithelial cells. IP3R1 and 2 are only weakly or not expressed in these cells. The antagonist of IP3R, 2APB, inhibited cell proliferation and induced apoptosis in gastric cancer cells from malignant ascites at concns.Several substances like 524-95-8 may be metioned in this study. of 100 mM to 100 mM in a dose-dependent manner. On the other hand, 2APB showed a weak effect on other gastric cancer cells established from primary tumors (SNU1), lymph node metastases or liver metastases (MKN1 or 74), mesothelial cell lines Met5A and myeloid leukemia HL60 cells. This suggests that this inhibitory effect depends on the level of IP3R3 expression. As cells which express IP3R3 mRNA (i.e. pancreas acinar 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 of an enzyme, such as protease, in gastric cancer cells. These results indicate that IP3R3 may be specifically involved in gastric cancer peritoneal dissemination and that IP3R3 may be a mol. target of the peritoneal dissemination of gastric cancer. Its antagonist, 2APB, may thus be useful for the specific treatment of peritoneal dissemination of gastric cancer. .