title: Paradoxically augmented anti-tumorigenic action of proton pump inhibitor and GastrininAPCMin/+ intestinal polyposis model.
abstract: Though long-term administration of proton pump inhibitor (PPI) imposed the risk of gastrointestinal track tumorigenesis by accompanied hypergastrinemia, no overt increases of colon cancer risk were witnessed after a long-term cohort study. Our recent investigation revealed that PPI prevented colitis-associated carcinogenesis through anti-inflammatory, anti-oxidative, and anti-mutagenic mechanisms in spite of hypergastrinemia. Therefore, we hypothesized that PPI might either antagonize the trophic action of gastrin on gastrointestinal tumorigenesis or synergize to exert augmented anti-tumorigenic actions. We challenged APCMin/+ mice with gastrin, PPI, PPI and gastrin together for 10 weeks and counted intestinal polyposis accompanied with molecular changes. Gastrin significantly increased intestinal polyposis, but combination of PPI and gastrin markedly attenuated intestinal polyposis compared to gastrin-promoted APCMin/+ mice (P<.001), in which significant β-catenin phosphorylation and inhibition of β-catenin nuclear translocation were observed with PPI alone or combination of PPI and gastrin, whereas gastrin treatment significantly increased β-catenin nuclear translocation. Significant footprints of apoptosis, G0/G1 accumulation, inactivation of p38 and extracellular signal-regulated kinase, decreased expressions of CD31, and inhibition of tumor necrosis factor-α and cyclooxygenase-2 were noted in the combination group. In vitro investigations were similar to in vivo findings as shown that PPI treatment inhibited the binding of gastrin to its receptor, inactivated β-catenin-associated signaling including Tcf/Lef and glycogen synthase kinase β, and paradoxically inhibited β-catenin-associated proliferative activities. Our investigations explain why colon cancer risk has not increased despite long-term use of PPIs and provide a rationale for using PPI to achieve anti-tumorigenesis beyond acid suppression.
authors.affiliation: CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, Seoul, South Korea ; College of Pharmacy, CHA University, Pocheon, South Korea.
authors.forename: Young-Min
authors.initials: YM
authors.lastname: Han
authors.affiliation: CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, Seoul, South Korea ; College of Pharmacy, CHA University, Pocheon, South Korea.
authors.forename: Ki Baik
authors.initials: KB
authors.lastname: Hahm
authors.affiliation: CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, Seoul, South Korea.
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Park
authors.affiliation: College of Pharmacy, CHA University, Pocheon, South Korea.
authors.forename: Sung Pyo
authors.initials: SP
authors.lastname: Hong
authors.affiliation: CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, Seoul, South Korea ; College of Pharmacy, CHA University, Pocheon, South Korea.
authors.forename: Eun-Hee
authors.initials: EH
authors.lastname: Kim
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000737:chemistry; D021581:Active Transport, Cell Nucleus; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005755:Gastrins / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D007249:Inflammation; D044483:Intestinal Polyposis / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000235:genetics*; D000077402:Pantoprazole; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D054328:Proton Pump Inhibitors / Q000737:chemistry*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000970:Antineoplastic Agents; C495267:CTNNB1 protein, mouse; D005755:Gastrins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D054328:Proton Pump Inhibitors; D014409:Tumor Necrosis Factor-alpha; D051176:beta Catenin; D000077402:Pantoprazole; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2