NADPH oxidase overexpression in human colon cancers and rat colon tumors induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP).

摘要: NADPH oxidase/dual-oxidase (Nox/Duox) family members have been implicated in nuclear factor kappa-B (NFκB)-mediated inflammation and inflammation-associated pathologies. We sought to examine, for the first time, role of Nox/Duox NFκB rats treated with cooked meat heterocyclic amine carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). In PhIP-induced colon tumors obtained after 1 year, Nox1, Nox4, NFκB-p50 NFκB-p65 were all highly overexpressed compared their levels adjacent normal-looking colonic mucosa. Nox1 Nox4 mRNA protein also markedly elevated a panel primary human cancers, matched controls. HT29 cancer cells, knockdown induced G1 cell cycle arrest, whereas Caco-2 cells there was strong apoptotic response, increased cleaved caspase-3, -6, -7 poly(ADP-ribose)polymerase. blocked lipopolysaccharide-induced phosphorylation IκB kinase, inhibited translocation (p50 p65) proteins, attenuated DNA binding activity. There corresponding reduction expression downstream targets, such as MYC, CCND1 IL1β. The results provide evidence carcinogenesis, including during early stages before tumor onset. Collectively, findings from this investigation others suggest that further work is warranted on development.