Carcinogenesis Advance Access originally published online on May 4, 2009
Carcinogenesis 2009 30(7):1209-1216; 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 Department of Oncologic Pathology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293, Japan
3 Department of Biochemical Science and Technology, Faculty of Agriculture, Kagoshima University, Korimoto 1-21-24, Kagoshima 890-0065, Japan
4 Gene Regulation Section, Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
5 Present address: Faculty of Biotechnology, Fukui Prefectual University, 1-1 Obama, Fukui 917-0003, Japan
* To whom correspondence should be addressed. Tel: +81 75 753 6283; Fax: +81 75 753 6284; Email: 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 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%, whereas LA was virtually inactive. 13-HOA (40 µM) inhibited TPA-induced activator protein-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 antitumor chemopreventive agent with a unique mode of action.
Abbreviations: AP-1, activator protein-1; DMBA, 7,12-dimethylbenz(a)anthracene; DMEM, Dulbecco's modified eagle medium; DMSO, dimethyl sulfoxide; EMEM, Eagle's minimum essential medium; ERK, extracellular signal-regulated kinase; FBS, fetal bovine serum; Fra-1, fos-like region antigen; 13-HOA, (±)-13-hydroxy-10-oxo-trans-11-octadecenoic acid; JNK, c-Jun N-terminal kinase; LA, linoleic acid; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; miR-21, microRNA-21; mRNA, messenger RNA; Myb, v-myb myeloblastosis viral oncogene homolog; PCNA, proliferating cell nuclear antigen; PCR, polymerase chain reaction; Pdcd4, programmed cell death 4; TPA, 12-O-tetradecanoylphorbol-13-acetate
Received January 22, 2009; revised April 15, 2009; accepted April 25, 2009.