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

TitleNADPH oxidase overexpression in human colon cancers and rat colon tumors induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP).
Publication TypeJournal Article
Year of Publication2011
AuthorsWang R, Dashwood W-M, Nian H, Löhr CV, Fischer KA, Tsuchiya N, Nakagama H, Ashktorab H, Dashwood RH
JournalInternational journal of cancer. Journal international du cancer
Volume128
Issue11
Pagination2581-90
Date Published2011 Jun 1
ISSN1097-0215
KeywordsAged, Aged, 80 and over, Animals, Apoptosis, Blotting, Western, Carcinogens, Case-Control Studies, Cell Cycle, Cell Proliferation, Colonic Neoplasms, Female, Humans, Imidazoles, Immunoenzyme Techniques, Male, Middle Aged, NADPH Oxidase, NF-kappa B p50 Subunit, Phosphorylation, Rats, Rats, Inbred F344, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, RNA, Small Interfering, Transcription Factor RelA
Abstract

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

DOI10.1002/ijc.25610
Alternate JournalInt. J. Cancer