Background/Aims: ω3-polyunsaturated fatty acids (ω3- PUFAs) are known to possess anticancer properties. However, the relationship between ω3-PUFAs and β-catenin, one of the key components of the Wnt signaling pathway, in human pancreatic cancer remains poorly characterized. Methods: Human pancreatic cancer cells (SW1990 and PANC-1) were exposed to two ω3-PUFAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), to investigate the relationship between ω3-PUFAs and the Wnt/β-catenin signaling pathway in vitro. Mouse pancreatic cancer (PANC02) cells were implanted into fat-1 transgenic mice, which express ω3 desaturases and result in elevated levels of ω3-PUFAs endogenously. The tumor size, levels of Wnt/β-catenin signaling molecules and apoptosis levels were analyzed to examine the influence of ω3-PUFAs in vivo. Results: DHA and EPA significantly inhibited cell growth and increased cell death in pancreatic cancer cells. DHA also reduced β-catenin expression, T cell factor/lymphoid-enhancing factor reporter activity and induced β-catenin/Axin/GSK-3β complex formation, a known precursor to β-catenin degradation. Furthermore, Wnt3a, a natural canonical Wnt pathway ligand, reversed DHA-induced growth inhibition in PANC-1 cells. Immunohistochemical analysis showed aberrant upregulation and increased nuclear staining of β-catenin in tumor tissues from pancreatic cancer patients. However, β-catenin levels in tumor tissues from fat-1 transgenic mice were reduced with a significant increase in apoptosis compared with those from control mice. Conclusion: ω3-PUFAs may be an effective therapy for the chemoprevention and treatment of human pancreatic cancer.

1.
Verma A, Guha S, Wang H, Fok JY, Koul D, Abbruzzese J, Mehta K: Tissue transglutaminase regulates focal adhesion kinase/AKT activation by modulating PTEN expression in pancreatic cancer cells. Clin Cancer Res 2008;14:1997–2005.
2.
Siegel R, Ward E, Brawley O, Jemal A: Cancer statistics: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 2011;61:212–236.
3.
Suzuki H, Masuda N, Shimura T, Araki K, Kobayashi T, Tsutsumi S, Asao T, Kuwano H: Nuclear beta-catenin expression at the invasive front and in the vessels predicts liver metastasis in colorectal carcinoma. Anticancer Res 2008;28:1821–1830.
4.
de La Coste A, Romagnolo B, Billuart P, Renard CA, Buendia MA, Soubrane O, Fabre M, Chelly J, Beldjord C, Kahn A, Perret C: Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci USA 1998;95:8847–8851.
5.
Schlange T, Matsuda Y, Lienhard S, Huber A, Hynes NE: Autocrine WNT signaling contributes to breast cancer cell proliferation via the canonical WNT pathway and EGFR transactivation. Breast Cancer Res 2007;9:R63.
6.
Zeng G, Germinaro M, Micsenyi A, Monga NK, Bell A, Sood A, Malhotra V, Sood N, Midda V, Monga DK, Kokkinakis DM, Monga SP: Aberrant Wnt/beta-catenin signaling in pancreatic adenocarcinoma. Neoplasia 2006;8:279–289.
7.
Akiyama T: Wnt/beta-catenin signaling. Cytokine Growth Factor Rev 2000;11:273–282.
8.
Huang H, He X: Wnt/beta-catenin signaling: new (and old) players and new insights. Curr Opin Cell Biol 2008;20:119–125.
9.
Huang D, Du X: Crosstalk between tumor cells and microenvironment via Wnt pathway in colorectal cancer dissemination. World J Gastroenterol 2008;14:1823–1827.
10.
Serini S, Trombino S, Oliva F, Piccioni E, Monego G, Resci F, Boninsegna A, Picci N, Ranelletti FO, Calviello G: Docosahexaenoic acid induces apoptosis in lung cancer cells by increasing MKP-1 and down-regulating p-ERK1/2 and p-p38 expression. Apoptosis 2008;13:1172–1183.
11.
Shaikh IA, Brown I, Schofield AC, Wahle KW, Heys SD: Docosahexaenoic acid enhances the efficacy of docetaxel in prostate cancer cells by modulation of apoptosis: the role of genes associated with the NF-kappaB pathway. Prostate 2008;68:1635–1646.
12.
Jakobsen CH, Storvold GL, Bremseth H, Follestad T, Sand K, Mack M, Olsen KS, Lundemo AG, Iversen JG, Krokan HE, Schonberg SA: DHA induces ER stress and growth arrest in human colon cancer cells: associations with cholesterol and calcium homeostasis. J Lipid Res 2008;49:2089–2100.
13.
Sun H, Berquin IM, Owens RT, O’Flaherty JT, Edwards IJ: Peroxisome proliferator-activated receptor gamma-mediated up-regulation of syndecan-1 by n–3 fatty acids promotes apoptosis of human breast cancer cells. Cancer Res 2008;68:2912–2919.
14.
Lim K, Han C, Xu L, Isse K, Demetris AJ, Wu T: Cyclooxygenase-2-derived prostaglandin E2 activates beta-catenin in human cholangiocarcinoma cells: evidence for inhibition of these signaling pathways by omega 3 polyunsaturated fatty acids. Cancer Res 2008;68:553–560.
15.
Calviello G, Resci F, Serini S, Piccioni E, Toesca A, Boninsegna A, Monego G, Ranelletti FO, Palozza P: Docosahexaenoic acid induces proteasome-dependent degradation of beta-catenin, down-regulation of survivin and apoptosis in human colorectal cancer cells not expressing COX-2. Carcinogenesis 2007;28:1202–1209.
16.
Lim K, Han C, Dai Y, Shen M, Wu T: Omega-3 polyunsaturated fatty acids inhibit hepatocellular carcinoma cell growth through blocking beta-catenin and cyclooxygenase-2. Mol Cancer Ther 2009;8:3046–3055.
17.
Lee JY, Kim JH, Chae G, Lee BK, Ha KS, Kwon YG, Kim YM: Cyclic AMP prolongs graft survival by suppressing apoptosis and inflammatory gene expression in acute cardiac allograft rejection. Exp Mol Med 2010;42:69–79.
18.
Nam E, Park C: Maspin suppresses survival of lung cancer cells through modulation of Akt pathway. Cancer Res Treat 2010;42:42–47.
19.
Moon KM, Seo HJ, Oh JY, Lee JS, Kim HY, Kim JH, Choi W, Kim BW, Kim KH, Lee JH: Autoimmune regulator gene (aire) is expressed in lymph node fibroblastic reticular cell, bls4. J Life Sci 2010;20:670–675.
20.
Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW: Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 1997;275:1787–1790.
21.
Weeraratna AT, Jiang Y, Hostetter G, Rosenblatt K, Duray P, Bittner M, Trent JM: Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma. Cancer Cell 2002;1:279–288.
22.
Lu D, Zhao Y, Tawatao R, Cottam HB, Sen M, Leoni LM, Kipps TJ, Corr M, Carson DA: Activation of the Wnt signaling pathway in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 2004;101:3118–3123.
23.
Behrens J, von Kries JP, Kuhl M, Bruhn L, Wedlich D, Grosschedl R, Birchmeier W: Functional interaction of beta-catenin with the transcription factor LEF-1. Nature 1996;382:638–642.
24.
Robinson JA, Chatterjee-Kishore M, Yaworsky PJ, Cullen DM, Zhao W, Li C, Kharode Y, Sauter L, Babij P, Brown EL, Hill AA, Akhter MP, Johnson ML, Recker RR, Komm BS, Bex FJ: Wnt/beta-catenin signaling is a normal physiological response to mechanical loading in bone. J Biol Chem 2006;281:31720–31728.
25.
Kang JX, Wang J, Wu L, Kang ZB: Transgenic mice: Fat-1 mice convert n-6 to n-3 fatty acids. Nature 2004;427:504.
26.
Kang JX: Fat-1 transgenic mice: a new model for omega-3 research. Prostaglandins Leukot Essent Fatty Acids 2007;77:263–267.
27.
Spencer L, Mann C, Metcalfe M, Webb M, Pollard C, Spencer D, Berry D, Steward W, Dennison A: The effect of omega-3 FAs on tumour angiogenesis and their therapeutic potential. Eur J Cancer 2009;45:2077–2086.
28.
Wall R, Ross RP, Fitzgerald GF, Stanton C: Fatty acids from fish: the anti-inflammatory potential of long-chain omega-3 fatty acids. Nutr Rev 2010;68:280–289.
29.
Gleissman H, Johnsen JI, Kogner P: Omega-3 fatty acids in cancer, the protectors of good and the killers of evil? Exp Cell Res 2010;316:1365–1373.
30.
Heller AR, Rossel T, Gottschlich B, Tiebel O, Menschikowski M, Litz RJ, Zimmermann T, Koch T: Omega-3 fatty acids improve liver and pancreas function in postoperative cancer patients. Int J Cancer 2004;111:611–616.
31.
Zhang W, Long Y, Zhang J, Wang C: Modulatory effects of EPA and DHA on proliferation and apoptosis of pancreatic cancer cells. J Huazhong Univ Sci Technolog Med Sci 2007;27:547–550.
32.
Merendino N, Loppi B, D’Aquino M, Molinari R, Pessina G, Romano C, Velotti F: Docosahexaenoic acid induces apoptosis in the human PaCa-44 pancreatic cancer cell line by active reduced glutathione extrusion and lipid peroxidation. Nutr Cancer 2005;52:225–233.
33.
Swamy MV, Citineni B, Patlolla JM, Mohammed A, Zhang Y, Rao CV: Prevention and treatment of pancreatic cancer by curcumin in combination with omega-3 fatty acids. Nutr Cancer 2008;60(suppl 1):81–89.
34.
Baumgartner M, Sturlan S, Roth E, Wessner B, Bachleitner-Hofmann T: Enhancement of arsenic trioxide-mediated apoptosis using docosahexaenoic acid in arsenic trioxide-resistant solid tumor cells. Int J Cancer 2004;112:707–712.
35.
Barker N, Clevers H: Mining the Wnt pathway for cancer therapeutics. Nat Rev Drug Discov 2006;5:997–1014.
36.
Fodde R, Brabletz T: Wnt/beta-catenin signaling in cancer stemness and malignant behavior. Curr Opin Cell Biol 2007;19:150–158.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.