Carcinogenesis Advance Access originally published online on March 28, 2008
Carcinogenesis 2008 29(5):1057-1063; doi:10.1093/carcin/bgn080
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Suppressive effects of nobiletin on hyperleptinemia and colitis-related colon carcinogenesis in male ICR mice
Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan
1 Department of Oncologic Pathology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293, Japan
2 Present address: Faculty of Biotechnology, Fukui Prefectural University, Fukui 910-1195, Japan
* To whom correspondence should be addressed. Tel: +81 75 753 6282; Fax: +81 75 753 6284; Email: cancer{at}kais.kyoto-u.ac.jp
Adipocytokines are a group of adipocyte-secreted proteins that have significant effects on the metabolism of lipids and carbohydrates, as well as numerous other processes. A number of recent studies have indicated that some adipocytokines may significantly influence the proliferation of malignant cells in vitro, whereas it remains unclear whether they have similar roles in vivo. In this study, we determined serum levels of adipocytokines in mice with azoxymethane (AOM)- and dextran sulfate sodium (DSS)-induced colon carcinogenesis. Five-week-old ICR mice were given a single intraperitoneal injection of AOM followed by 1% DSS in drinking water for 7 days. Nobiletin (NOB), a citrus flavonoid, was given in the diet (100 p.p.m) for 17 weeks. Thereafter, the incidence and number of colon tumors and serum concentration of adipocytokines were determined at the end of week 20. The serum leptin level in AOM/DSS-treated mice was six times higher than that in untreated mice, whereas there were no significant differences in the levels of triglycerides, adiponectin and interleukin-6. Feeding with NOB abolished colonic malignancy and notably decreased the serum leptin level by 75%. Further, NOB suppressed the leptin-dependent, but not independent, proliferation of HT-29 colon cancer cells and decreased leptin secretion through inactivation of mitogen-activated protein kinase/extracellular signaling-regulated protein kinase, but not that of adiponectin in differentiated 3T3-L1 mouse adipocytes in a dose-dependent manner. Taken together, our results suggest that higher levels of leptin in serum promote colon carcinogenesis in mice, whereas NOB has chemopreventive effects against colon carcinogenesis, partly through regulation of leptin levels.
Abbreviations: AOM, azoxymethane; DMEM, Dulbecco's modified Eagle medium; DSS, dextran sulfate sodium; eIF4B, eukaryotic initiation factor 4B; ERK, extracellular signal-regulated protein kinase; FBS, fetal bovine serum; IL-6, interleukin-6; MEK, mitogen-activated protein kinase/extracellular signaling-regulated protein kinase kinase; mTOR, mammalian target of rapamycin; NOB, nobiletin; Ob-R, leptin receptor; TNF-
, tumor necrosis factor-
Received October 15, 2007; revised February 15, 2008; accepted March 12, 2008.
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