title: 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.
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.
authors.affiliation: Division of Cancer Development System, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Igarashi
authors.affiliation: Division 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.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hippo
authors.affiliation: Division of Cancer Development System, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Ochiai
authors.affiliation: Division of Cancer Development System, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Fukuda
authors.affiliation: Division of Cancer Development System, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakagama
mesh_terms: D058739:Aberrant Crypt Foci / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D063646:Carcinogenesis / Q000187:drug effects / Q000473:pathology*; D002273:Carcinogens / Q000633:toxicity*; D002460:Cell Line; D003106:Colon / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000473:pathology; D004032:Diet; D059305:Diet, High-Fat; D004198:Disease Susceptibility / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000633:toxicity*; D008297:Male; D009765:Obesity / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D002273:Carcinogens; D007093:Imidazoles; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D051057:Proto-Oncogene Proteins c-akt
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