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http://dx.doi.org/10.5352/JLS.2013.23.5.689

Cytotoxic Mechanism of Docosahexaenoic Acid in Human Oral Cancer Cells  

Hong, Tae-Hwa (Department of Biochemisty, College of Medicine, Chungnam National University)
Kim, Hoon (Department of Biochemisty, College of Medicine, Chungnam National University)
Shin, Soyeon (Department of Biochemisty, College of Medicine, Chungnam National University)
Jing, Kaipeng (Department of Biochemisty, College of Medicine, Chungnam National University)
Jeong, Soyeon (Department of Biochemisty, College of Medicine, Chungnam National University)
Lim, Hyun (Department of Biochemisty, College of Medicine, Chungnam National University)
Yun, Donghyuk (Department of Biochemisty, College of Medicine, Chungnam National University)
Jeong, Ki-Eun (Department of Biochemisty, College of Medicine, Chungnam National University)
Lee, Myung-Ryul (Department of Biochemisty, College of Medicine, Chungnam National University)
Park, Jong-Il (Department of Biochemisty, College of Medicine, Chungnam National University)
Kweon, Gi-Ryang (Department of Biochemisty, College of Medicine, Chungnam National University)
Park, Seung Kiel (Department of Biochemisty, College of Medicine, Chungnam National University)
Hwang, Byung-Doo (Department of Biochemisty, College of Medicine, Chungnam National University)
Lim, Kyu (Department of Biochemisty, College of Medicine, Chungnam National University)
Publication Information
Journal of Life Science / v.23, no.5, 2013 , pp. 689-697 More about this Journal
Abstract
In the United States, about 40,000 new cases of oral cancer are diagnosed each year and nearly 7,800 patients died from it in 2012. Omega-3 polyunsaturated fatty acids have been found to have anticancer effects in a variety of cancer cell lines and animal models, but their effect in oral cancer remains unclear. This study was designed to examine the effect of docosahexaenoic acid (DHA, a kind of omega-3 fatty acid) on oral cancer cells and the molecular mechanism of its action. We found that exposure of squamous cell carcinoma-4 (SCC-4) and squamous cell carcinoma-9 (SCC-9) human oral cancer cells to DHA induced growth inhibition in a dose- and time-dependent manner. Meanwhile, in addition to the elevated levels of apoptotic markers, such as cleaved PARP, subG1 portion and TUNEL-positive nuclei, DHA led to autophagic vesicle formation and an increase in autophagic flux, indicating the involvement of both apoptosis and autophagy in the inhibitory effects of DHA on oral cancer cells. Further experiments revealed that the apoptosis and autophagy induced by DHA were linked to inhibition of mammalian target of rapamycin (mTOR) signaling by AKT inhibition and AMP-activated protein kinase (AMPK) activation in SCC-9 cells. Together, our results suggest that DHA induces apoptosis- and autophagy-associated cell death through the AMPK/AKT/mTOR signaling pathway in oral cancer cells. Thus, utilization of omega-3 fatty acids may represent a promising therapeutic approach for chemoprevention and treatment of human oral cancer.
Keywords
AMP-activated protein kinase (AMPK); AKT; autophagy; DHA; mammalian target of rapamycin (mTOR);
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1 Narayanan, B. A., Narayanan, N. K., Desai, D., Pittman, B. and Reddy, B. S. 2004. Effects of a combination of docosahexaenoic acid and 1,4-phenylene bis(methylene) selenocyanate on cyclooxygenase 2, inducible nitric oxide synthase and beta-catenin pathways in colon cancer cells. Carcinogenesis 25, 2443-2449.   DOI   ScienceOn
2 Narayanan, B. A., Narayanan, N. K., Simi, B. and Reddy, B. S. 2003. Modulation of inducible nitric oxide synthase and related proinflammatory genes by the omega-3 fatty acid docosahexaenoic acid in human colon cancer cells. Cancer Res 63, 972-979.
3 Papandreou, I., Lim, A. L., Laderoute, K. and Denko, N. C. 2008. Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L. Cell Death Differ 15, 1572-1581.   DOI   ScienceOn
4 Rose, D. P. and Connolly, J. M. 1999. Omega-3 fatty acids as cancer chemopreventive agents. Pharmacol Ther 83, 217-244.   DOI   ScienceOn
5 Shin, S. Y., Kim, Y. J., Song, K. S., Jing, K., Kim, N. Y., Jeong, S. Y., Park, J. H., Seo, K. S., Heo, J. Y., Kwon, H. J., Park,J. I., Kweon, G. R., Yoon, W. H., Hwang, B. D, Lim, K. 2010. Mechanism of anti-invasive action of docosahexaenoic acid in SW480 human colon cancer cell. J Life Sci 20, 561-571.   과학기술학회마을   DOI   ScienceOn
6 Siegel, R., Naishadham, D. and Jemal, A. 2012. Cancer statistics, 2012. CA Cancer J Clin 62, 10-29.   DOI   ScienceOn
7 Song, K. S., Jing, K., Kim, J. S., Yun, E. J., Shin, S., Seo, K. S., Park, J. H., Heo, J. Y., Kang, J. X., Suh, K. S., Wu, T., Park, J. I., Kweon, G. R., Yoon, W. H., Hwang, B. D. and Lim, K. 2011. Omega-3-polyunsaturated fatty acids suppress pancreatic cancer cell growth in vitro and in vivo via downregulation of Wnt/Beta-catenin signaling. Pancreatology 11, 574-584.   DOI   ScienceOn
8 Tevar, R., Jho, D. H., Babcock, T., Helton, W. S. and Espat, N. J. 2002. Omega-3 fatty acid supplementation reduces tumor growth and vascular endothelial growth factor expression in a model of progressive non-metastasizing malignancy. JPEN J Parenter Enteral Nutr 26, 285-289.   DOI
9 Xia, S. H., Wang, J. and Kang, J. X. 2005. Decreased n-6/n-3 fatty acid ratio reduces the invasive potential of human lung cancer cells by downregulation of cell adhesion/invasion- related genes. Carcinogenesis 26, 779-784.   DOI   ScienceOn
10 Zhang, X., Liu, Y., Gilcrease, M. Z., Yuan, X. H., Clayman, G. L., Adler-Storthz, K. and Chen, Z. 2002. A lymph node metastatic mouse model reveals alterations of metastasis- related gene expression in metastatic human oral carcinoma sublines selected from a poorly metastatic parental cell line. Cancer 95, 1663-1672.   DOI   ScienceOn
11 Kobayashi, N., Barnard, R. J., Henning, S. M., Elashoff, D., Reddy, S. T., Cohen, P., Leung, P., Hong-Gonzalez, J., Freedland, S. J., Said, J., Gui, D., Seeram, N. P., Popoviciu, L. M., Bagga, D., Heber, D., Glaspy, J. A. and Aronson, W. J. 2006. Effect of altering dietary omega-6/omega-3 fatty acid ratios on prostate cancer membrane composition, cyclooxygenase- 2, and prostaglandin E2. Clin Cancer Res 12, 4662-4670.   DOI   ScienceOn
12 Kroemer, G., Galluzzi, L., Vandenabeele, P., Abrams, J., Alnemri, E. S., Baehrecke, E. H., Blagosklonny, M. V., El-Deiry, W. S., Golstein, P., Green, D. R., Hengartner, M., Knight, R. A., Kumar, S., Lipton, S. A., Malorni, W., Nunez, G., Peter, M. E., Tschopp, J., Yuan, J., Piacentini, M., Zhivotovsky, B. and Melino, G. 2009. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ 16, 3-11.   DOI   ScienceOn
13 Lim, K., Han, C., Xu, L., Isse, K., Demetris, A. J. and Wu, T. 2008. 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 68, 553-560.   DOI   ScienceOn
14 Kromhout, D. 1990. The importance of N-6 and N-3 fatty acids in carcinogenesis. Med Oncol Tumor Pharmacother 7, 173-176.
15 Larsson, S. C., Kumlin, M., Ingelman-Sundberg, M. and Wolk, A. 2004. Dietary long-chain n-3 fatty acids for the prevention of cancer: a review of potential mechanisms. Am J Clin Nutr 79, 935-945.
16 Lim, K., Han, C., Dai, Y., Shen, M. and Wu, T. 2009. Omega-3 polyunsaturated fatty acids inhibit hepatocellular carcinoma cell growth through blocking beta-catenin and cyclooxygenase-2. Mol Cancer Ther 8, 3046-3055.   DOI   ScienceOn
17 Lipworth, L. 1995. Epidemiology of breast cancer. Eur J Cancer Prev 4, 7-30.   DOI
18 Liu, G., Bibus, D. M., Bode, A. M., Ma, W. Y., Holman, R. T. and Dong, Z. 2001. Omega 3 but not omega 6 fatty acids inhibit AP-1 activity and cell transformation in JB6 cells. Proc Natl Acad Sci USA 98, 7510-7515.   DOI   ScienceOn
19 McCabe, A. J., Wallace, J. M., Gilmore, W. S., McGlynn, H. and Strain, S. J. 2005. Docosahexaenoic acid reduces in vitro invasion of renal cell carcinoma by elevated levels of tissue inhibitor of metalloproteinase-1. J Nutr Biochem 16, 17-22.   DOI   ScienceOn
20 Meley, D., Bauvy, C., Houben-Weerts, J. H., Dubbelhuis, P. F., Helmond, M. T., Codogno, P. and Meijer, A. J. 2006. AMP-activated protein kinase and the regulation of autophagic proteolysis. J Biol Chem 281, 34870-34879.   DOI   ScienceOn
21 Minami, Y., Nishino, Y., Tsubono, Y., Tsuji, I. and Hisamichi, S. 2006. Increase of colon and rectal cancer incidence rates in Japan: trends in incidence rates in Miyagi Prefecture, 1959-1997. J Epidemiol 16, 240-248.   DOI
22 Choi, K. S. 2012. Autophagy and cancer. Exp Mol Med 44, 109-120.   DOI   ScienceOn
23 Mukutmoni-Norris, M., Hubbard, N. E. and Erickson, K. L. 2000. Modulation of murine mammary tumor vasculature by dietary n-3 fatty acids in fish oil. Cancer Lett 150, 101-109.   DOI   ScienceOn
24 Calviello, G., Di Nicuolo, F., Gragnoli, S., Piccioni, E., Serini, S., Maggiano, N., Tringali, G., Navarra, P., Ranelletti, F. O. and Palozza, P. 2004. n-3 PUFAs reduce VEGF expression in human colon cancer cells modulating the COX-2/PGE2 induced ERK-1 and -2 and HIF-1alpha induction pathway. Carcinogenesis 25, 2303-2310.   DOI   ScienceOn
25 Chen, P. N., Hsieh, Y. S., Chiang, C. L., Chiou, H. L., Yang, S. F. and Chu, S. C. 2006. Silibinin inhibits invasion of oral cancer cells by suppressing the MAPK pathway. J Dent Res 85, 220-225.   DOI   ScienceOn
26 Collett, E. D., Davidson, L. A., Fan, Y. Y., Lupton, J. R. and Chapkin, R. S. 2001. n-6 and n-3 polyunsaturated fatty acids differentially modulate oncogenic Ras activation in colonocytes. Am J Physiol Cell Physiol 280, C1066-1075.
27 Davidson, L. A., Wang, N., Shah, M. S., Lupton, J. R., Ivanov, I. and Chapkin, R. S. 2009. n-3 Polyunsaturated fatty acids modulate carcinogen-directed non-coding microRNA signatures in rat colon. Carcinogenesis 30, 2077-2084.   DOI   ScienceOn
28 Farago, N., Feher, L. Z., Kitajka, K., Das, U. N. and Puskas, L. G. 2011. MicroRNA profile of polyunsaturated fatty acid treated glioma cells reveal apoptosis-specific expression changes. Lipids Health Dis 10, 173.   DOI
29 Gago-Dominguez, M., Yuan, J. M., Sun, C. L., Lee, H. P. and Yu, M. C. 2003. Opposing effects of dietary n-3 and n-6 fatty acids on mammary carcinogenesis: The Singapore Chinese Health Study. Br J Cancer 89, 1686-1692.   DOI   ScienceOn
30 Ge, Y., Chen, Z., Kang, Z. B., Cluette-Brown, J., Laposata, M. and Kang, J. X. 2002. Effects of adenoviral gene transfer of C. elegans n-3 fatty acid desaturase on the lipid profile and growth of human breast cancer cells. Anticancer Res 22, 537-543.
31 Hammamieh, R., Chakraborty, N., Miller, S. A., Waddy, E., Barmada, M., Das, R., Peel, S. A., Day, A. A. and Jett, M. 2007. Differential effects of omega-3 and omega-6 Fatty acids on gene expression in breast cancer cells. Breast Cancer Res Treat 101, 7-16.   DOI
32 He, C. and Klionsky, D. J. 2009. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 43, 67-93.   DOI   ScienceOn
33 Jing, K. and Lim, K. 2012. Why is autophagy important in human diseases? Exp Mol Med 44, 69-72.   DOI   ScienceOn
34 Jing, K., Song, K. S., Shin, S., Kim, N., Jeong, S., Oh, H. R., Park, J. H., Seo, K. S., Heo, J. Y., Han, J., Park, J. I., Han, C., Wu, T., Kweon, G. R., Park, S. K., Yoon, W. H., Hwang, B. D. and Lim, K. 2011. Docosahexaenoic acid induces autophagy through p53/AMPK/mTOR signaling and promotes apoptosis in human cancer cells harboring wild-type p53. Autophagy 7, 1348-1358.   DOI   ScienceOn
35 Kamada, Y., Funakoshi, T., Shintani, T., Nagano, K., Ohsumi, M. and Ohsumi, Y. 2000. Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J Cell Biol 150, 1507-1513.   DOI   ScienceOn
36 Klionsky, D. J., Abeliovich, H., Agostinis, P., Agrawal, D. K., Aliev, G., Askew, D. S., Baba, M., Baehrecke, E. H., Bahr, B. A., Ballabio, A., Bamber, B. A., Bassham, D. C., Bergamini, E., Bi, X., Biard-Piechaczyk, M., Blum, J. S., Bredesen, D. E., Brodsky, J. L., Brumell, J. H., Brunk, U. T., Bursch, W., Camougrand, N., Cebollero, E., Cecconi, F., Chen, Y., Chin, L. S., Choi, A., Chu, C. T., Chung, J., Clarke, P. G., Clark, R. S., Clarke, S. G., Clave, C., Cleveland, J. L., Codogno, P., Colombo, M. I., Coto-Montes, A., Cregg, J. M., Cuervo, A. M., Debnath, J., Demarchi, F., Dennis, P. B., Dennis, P. A., Deretic, V., Devenish, R. J., Di Sano, F., Dice, J. F., Difiglia, M., Dinesh-Kumar, S., Distelhorst, C. W., Djavaheri-Mergny, M., Dorsey, F. C., Droge, W., Dron, M., Dunn, W. A., Jr., Duszenko, M., Eissa, N. T., Elazar, Z., Esclatine, A., Eskelinen, E. L., Fesus, L., Finley, K. D., Fuentes, J. M., Fueyo, J., Fujisaki, K., Galliot, B., Gao, F. B., Gewirtz, D. A., Gibson, S. B., Gohla, A., Goldberg, A. L., Gonzalez, R., Gonzalez-Estevez, C., Gorski, S., Gottlieb, R. A., Haussinger, D., He, Y. W., Heidenreich, K., Hill, J. A., Hoyer-Hansen, M., Hu, X., Huang, W. P., Iwasaki, A., Jaattela, M., Jackson, W. T., Jiang, X., Jin, S., Johansen, T., Jung, J. U., Kadowaki, M., Kang, C., Kelekar, A., Kessel, D. H., Kiel, J. A., Kim, H. P., Kimchi, A., Kinsella, T. J., Kiselyov, K., Kitamoto, K., Knecht, E., Komatsu, M., Kominami, E., Kondo, S., Kovacs, A. L., Kroemer, G., Kuan, C. Y., Kumar, R., Kundu, M., Landry, J., Laporte, M., Le, W., Lei, H. Y., Lenardo, M. J., Levine, B., Lieberman, A., Lim, K. L., Lin, F. C., Liou, W., Liu, L. F., Lopez-Berestein, G., Lopez-Otin, C., Lu, B., Macleod, K. F., Malorni, W., Martinet, W., Matsuoka, K., Mautner, J., Meijer, A. J., Melendez, A., Michels, P., Miotto, G., Mistiaen, W. P., Mizushima, N., Mograbi, B., Monastyrska, I., Moore, M. N., Moreira, P. I., Moriyasu, Y., Motyl, T., Munz, C., Murphy, L. O., Naqvi, N. I., Neufeld, T. P., Nishino, I., Nixon, R. A., Noda, T., Nurnberg, B., Ogawa, M., Oleinick, N. L., Olsen, L. J., Ozpolat, B., Paglin, S., Palmer, G. E., Papassideri, I., Parkes, M., Perlmutter, D. H., Perry, G., Piacentini, M., Pinkas-Kramarski, R., Prescott, M., Proikas-Cezanne, T., Raben, N., Rami, A., Reggiori, F., Rohrer, B., Rubinsztein, D. C., Ryan, K. M., Sadoshima, J., Sakagami, H., Sakai, Y., Sandri, M., Sasakawa, C., Sass, M., Schneider, C., Seglen, P. O., Seleverstov, O., Settleman, J., Shacka, J. J., Shapiro, I. M., Sibirny, A., Silva-Zacarin, E. C., Simon, H. U., Simone, C., Simonsen, A., Smith, M. A., Spanel-Borowski, K., Srinivas, V., Steeves, M., Stenmark, H., Stromhaug, P. E., Subauste, C. S., Sugimoto, S., Sulzer, D., Suzuki, T., Swanson, M. S., Tabas, I., Takeshita, F., Talbot, N. J., Talloczy, Z., Tanaka, K., Tanida, I., Taylor, G. S., Taylor, J. P., Terman, A., Tettamanti, G., Thompson, C. B., Thumm, M., Tolkovsky, A. M., Tooze, S. A., Truant, R., Tumanovska, L. V., Uchiyama, Y., Ueno, T., Uzcategui, N. L., van der Klei, I., Vaquero, E. C., Vellai, T., Vogel, M. W., Wang, H. G., Webster, P., Wiley, J. W., Xi, Z., Xiao, G., Yahalom, J., Yang, J. M., Yap, G., Yin, X. M., Yoshimori, T., Yu, L., Yue, Z., Yuzaki, M., Zabirnyk, O., Zheng, X., Zhu, X. and Deter, R. L. 2008. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 4, 151-175.   DOI
37 Bartsch, H., Nair, J. and Owen, R. W. 1999. Dietary polyunsaturated fatty acids and cancers of the breast and colorectum: emerging evidence for their role as risk modifiers. Carcinogenesis 20, 2209-2218.   DOI   ScienceOn
38 Bougnoux, P. 1999. n-3 polyunsaturated fatty acids and cancer. Curr Opin Clin Nutr Metab Care 2, 121-126.   DOI   ScienceOn