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http://dx.doi.org/10.5352/JLS.2012.22.8.1018

Snail Switches 5-FU-induced Apoptosis to Necrosis through Akt/PKB Activation and p53 Down-regulation  

Lee, Su-Yeon (Department of Molecular Biology, College of Natural Sciences, Pusan National University)
Jeon, Hyun-Min (Department of Molecular Biology, College of Natural Sciences, Pusan National University)
Ju, Min-Kyung (Department of Molecular Biology, College of Natural Sciences, Pusan National University)
Kim, Cho-Hee (Department of Molecular Biology, College of Natural Sciences, Pusan National University)
Jeong, Eui-Kyong (Department of Molecular Biology, College of Natural Sciences, Pusan National University)
Park, Hye-Gyeong (Nanobiotechnology Center, Pusan National University)
Kang, Ho-Sung (Department of Molecular Biology, College of Natural Sciences, Pusan National University)
Publication Information
Journal of Life Science / v.22, no.8, 2012 , pp. 1018-1023 More about this Journal
Abstract
Snail is a zinc finger transcription factor that induces epithelial-to-mesenchymal transition (EMT), which promotes tumor invasion and metastasis by repressing E-cadherin expression. In addition, Snail restricts the cellular apoptotic response to apoptotic stimuli or survival factor withdrawal; however, its molecular mechanism remains largely unknown. In this study, we have investigated the mechanism underlying Snail-mediated chemoresistance to 5-fluorouracil (5-FU), one of the most widely used anti-cancer drugs. When Snail was overexpressed by doxycycline (DOX) in MCF-7 #5 cells, it inhibited 5-FU-induced apoptotic cell death and switched the cell death mode to necrosis. Snail expression, either by DOX treatment in MCF-7 #5 cells or by the transfection of Snail expression vectors pCR3.1-Snail-Flg, phosphorylation-resistant pCR3.1-S104, and 107A Snail-Flg in MCF-7 cells specifically induced PTEN down-regulation/inactivation and Akt/PKB activation, without affecting ERK1/2 activity. In addition, Snail prominently suppressed 5-FU-induced increases in p53 levels. These findings demonstrate that Snail switches 5-FU-induced apoptosis to necrosis through the activation of Akt/PKB and the down-regulation of p53 levels.
Keywords
Snail; 5-fluorouracil (5-FU); apoptosis/necrosis; Akt/PKB; p53;
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1 Balmanno, K. and Cook, S. J. 2009. Tumour cell survival signalling by the ERK1/2 pathway. Cell Death Differ. 16, 368-377.   DOI
2 Escriva, M., Peiro, S., Herranz, N., Villagrasa, P., Dave, N., Montserrat-Sentis, B., Murray, S. A., Franci, C., Gridley, T., Virtanen, I. and Garcia de Herreros, A. 2008. Repression of PTEN phosphatase by Snail1 transcriptional factor during gamma radiation-induced apoptosis. Mol. Cell. Biol. 28, 1528-1540.   DOI
3 Gottlieb, T. M., Leal, J. F., Seger, R., Taya, Y. and Oren, M. 2002. Cross-talk between Akt, p53 and Mdm2: possible implications for the regulation of apoptosis. Oncogene 21, 1299-1303.   DOI
4 Hoshino, H., Miyoshi, N., Nagai, K., Tomimaru, Y., Nagano, H., Sekimoto, M., Doki, Y., Mori, M. and Ishii, H. 2009. Epithelial-mesenchymal transition with expression of SNAI1-induced chemoresistance in colorectal cancer. Biochem. Biophys. Res. Commun. 390, 1061-1065.   DOI
5 Kajita, M., McClinic, K. N. and Wade, P. A. 2004. Aberrant expression of the transcription factors snail and slug alters the response to genotoxic stress. Mol. Cell. Biol. 24, 7559-7566.   DOI
6 Kim, C. H., Jeon, H. M., Lee, S. Y., Ju, M. K., Moon, J. Y., Park, H. G., Yoo, M. A., Choi, B. T., Yook, J. I., Lim, S. C., Han, S. I. and Kang, H. S. 2011. Implication of snail in metabolic stress-induced necrosis. PLoS One 6, e18000.   DOI
7 Kurrey, N. K., Jalgaonkar, S. P., Joglekar, A. V., Ghanate, A. D., Chaskar, P. D., Doiphode, R. Y. and Bapat, S. A. 2009. Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. Stem Cells 27, 2059-2068.   DOI   ScienceOn
8 Lee, S. Y., Jeong, E. K., Jeon, H. M., Kim, C. H. and Kang, H. S. 2010. Implication of necrosis-linked p53 aggregation in acquired apoptotic resistance to 5-FU in MCF-7 multicellular tumour spheroids. Oncol. Rep. 24, 73-79.
9 Lee, S. Y., Jeon, H. M., Ju, M. K., Kim, C. H., Yoon, G., Han, S. I., Park, H. G. and Kang, H. S. 2012. Wnt/snail signaling regulates cytochrome c oxidase and glucose metabolism. Cancer Res. 72, 3607-3617.   DOI   ScienceOn
10 Levine, A. J., Feng, Z., Mak, T. W., You, H. and Jin, S. 2006. Coordination and communication between the p53 and IGF-1-AKT-TOR signal transduction pathways. Genes Dev. 20, 267-275.   DOI
11 Longley, D. B., Harkin, D. P. and Johnston, P. G. 2003. 5-fluorouracil: mechanisms of action and clinical strategies. Nat. Rev. Cancer 3, 330-338.   DOI   ScienceOn
12 Pelicano, H., Xu, R. H., Du, M., Feng, L., Sasaki, R., Carew, J. S., Hu, Y., Ramdas, L., Hu, L., Keating, M. J., Zhang, W., Plunkett, W. and Huang, P. 2006. Mitochondrial respiration defects in cancer cells cause activation of Akt survival pathway through a redox-mediated mechanism. J. Cell Biol. 175, 913-923.   DOI
13 Lotze, M. T. and Tracey, K. J. 2005. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat. Rev. Immunol. 5, 331-342.   DOI
14 Nieto, M. A. 2002. The snail superfamily of zinc-finger transcription factors. Nat. Rev. Mol. Cell. Biol. 3, 155-166.   DOI
15 Peinado, H., Olmeda, D. and Cano, A. 2007. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat. Rev. Cancer 7, 415-428.   DOI
16 Qiu, W., Leibowitz, B., Zhang, L. and Yu, J. 2010. Growth factors protect intestinal stem cells from radiation-induced apoptosis by suppressing PUMA through the PI3K/AKT/p53 axis. Oncogene 29, 1622-1632.   DOI
17 Raguz, S. and Yague, E. 2008. Resistance to chemotherapy: new treatments and novel insights into an old problem. Br. J. Cancer 99, 387-391.   DOI   ScienceOn
18 Scaffidi, P., Misteli, T. and Bianchi, M. E. 2002. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418, 191-195.   DOI   ScienceOn
19 Vakkila, J. and Lotze, M. T. 2004. Inflammation and necrosis promote tumour growth. Nat. Rev. Immunol. 4, 641-648.   DOI
20 Vega, S., Morales, A. V., Ocana, O. H., Valdes, F., Fabregat, I. and Nieto, M. A. 2004. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev. 18, 1131-1143.   DOI
21 Yamaguchi, H. and Wang, H. G. 2001. The protein kinase PKB/Akt regulates cell survival and apoptosis by inhibiting Bax conformational change. Oncogene 20, 7779-7786.   DOI
22 Vivanco, I. and Sawyers, C. L. 2002. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat. Rev. Cancer 2, 489-501.   DOI   ScienceOn
23 Wilson, T. R., Longley, D. B. and Johnston, P. G. 2006. Chemoresistance in solid tumours. Ann. Oncol. 17 Suppl 10, x315-324.   DOI
24 Wu, W. S., Heinrichs, S., Xu, D., Garrison, S. P., Zambetti, G. P., Adams, J. M. and Look, A. T. 2005. Slug antagonizes p53-mediated apoptosis of hematopoietic progenitors by repressing puma. Cell 123, 641-653.   DOI
25 Yook, J. I., Li, X. Y., Ota, I., Hu, C., Kim, H. S., Kim, N. H., Cha, S. Y., Ryu, J. K., Choi, Y. J., Kim, J., Fearon, E. R. and Weiss, S. J. 2006. A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells. Nat. Cell Biol. 8, 1398-1406.   DOI
26 Zhang, N., Yin, Y., Xu, S. J. and Chen, W. S. 2008. 5-Fluorouracil: mechanisms of resistance and reversal strategies. Molecules 13, 1551-1569.   DOI   ScienceOn
27 Zong, W. X., Ditsworth, D., Bauer, D. E., Wang, Z. Q. and Thompson, C. B. 2004. Alkylating DNA damage stimulates a regulated form of necrotic cell death. Genes Dev. 18, 1272-1282.   DOI   ScienceOn