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.