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Biochem Biophys Res Commun. 2014 Jan 17;443(3):852-7. doi: 10.1016/j.bbrc.2013.12.059. Epub 2013 Dec 14.

AKT is critically involved in cooperation between obesity and the dietary carcinogen amino-1-methyl-6-phenylimidazo [4,5-b] (PhIP) toward colon carcinogenesis in rats.

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  • 1Division of Cancer Development System, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
  • 2Division of Cancer Development System, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Electronic address: yhippo@ncc.go.jp.

Abstract

Obesity is highly associated with colon cancer development. Whereas it is generally attributed to pro-tumorigenic effects of high fat diet (HFD), we here show that a common genetic basis for predisposition to obesity and colon cancer might also underlie the close association. Comparison across multiple rat strains revealed that strains prone to colon tumorigenesis initiated by a dietary carcinogen amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) tended to develop obesity. Through transcriptome and extensive immunoblotting analyses, we identified the basal level of activated AKT in colonic crypts as a biomarker for the common predisposition. Notably, PhIP induced activation of AKT, which could persist for several weeks under a low fat diet (LFD), but not under HFD. On the other hand, PhIP and HFD independently induced Wnt pathway activation and inhibited apoptosis, through distinct mechanisms involving GSK-3β, caspase 3 and poly-ADP ribose polymerase (PARP). Taken together, these observations provide mechanistic insights into how PhIP-induced activation of AKT might cooperate with HFD at multiple levels toward development of colon cancer.

Copyright © 2013 Elsevier Inc. All rights reserved.

KEYWORDS:

ACF; AKT; Colon cancer; GSEA; HCA; Obesity; PhIP; Rat; Susceptibility; aberrant crypt foci; amino-1-methyl-6-phenylimidazo [4,5-b] pyridine; gene set enrichment analysis; heterocyclic amine

PMID:
24342614
[PubMed - indexed for MEDLINE]
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