Carcinogenesis Advance Access published online on May 4, 2009
Carcinogenesis, doi:10.1093/carcin/bgp106
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Linoleic acid metabolite suppresses skin inflammation and tumor promotion in mice: Possible roles of programmed cell death 4 induction
1 Division of Food Science and Biotechnology, Graduate School of Agriculture,Kyoto University, Kyoto 606-8502, Japan
2 Present address: Faculty of Biotechnology, Fukui Prefectual University, 1-1 Obama, Fukui 917-0003, Japan
3 Department of Oncologic Pathology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293, Japan
4 Department of Biochemical Science and Technology, Faculty of Agriculture, Kagoshima University, Korimoto 1-21-24, Kagoshima 890-0065, Japan
5 Gene Regulation Section, Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, USA
* Corresponding author (A. Murakami). Fax: +81 75 753 6284 Tel: +81 75 753 6283 E-mail address: cancer{at}kais.kyoto-u.ac.jp
(±)-13-Hydroxy-10-oxo-trans-11-octadecenoic acid (13-HOA) is one of the lipoxygenase metabolites of linoleic acid (LA) from corn germ. Recently, we reported that this metabolite suppressed the expression of lipopolysaccharide-induced proinflammatory genes in murine macrophages by disrupting mitogen-activated protein kinases (MAPKs) and Akt pathways. In this study, we investigated the inhibitory effects of 13-HOA on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation in ears and skin, as well as tumor promotion in female ICR mice. Pretreatment with 13-HOA (1600 nmol) inhibited ear edema formation by 95% (P < 0.05) in an inflammation test, and reduced tumor incidence and the number of tumors per mouse by 40% and 64% (P < 0.05 each), respectively, in a two-stage skin carcinogenesis model. Histological examinations revealed that it decreased epidermal thickness, the number of infiltrated leukocytes, and cell proliferation index. Furthermore, 13-HOA (8-40 µM) suppressed TPA-induced anchorage-independent growth of JB6 mouse epidermal cells by 70-100%, while LA was virtually inactive. 13-HOA (40 µM) inhibited TPA-induced AP-1 transactivation, but not extracellular signal-regulated kinase1/2 activation. Interestingly, 13-HOA (40 µM and 1600 nmol in JB6 cells and mouse skin, respectively) induced expression of programmed cell death 4 (Pdcd4), a novel tumor suppressor protein. To our knowledge, this is the first report of a food factor that is able to induce Pdcd4 expression. Collectively, our results indicate that 13-HOA may be a novel anti-inflammatory and anti-tumor chemopreventive agent with a unique mode of action.
Key Words: linoleic acid • chemoprevention • skin carcinogenesis • JB6 cell • Pdcd4
Received January 22, 2009; revised April 15, 2009; accepted April 25, 2009.