Browse > Article
http://dx.doi.org/10.4062/biomolther.2014.117

Cardamonin Suppresses TGF-β1-Induced Epithelial Mesenchymal Transition via Restoring Protein Phosphatase 2A Expression  

Kim, Eun Ji (BK21PLUS R-FIND Team, College of Pharmacy, Dongguk University)
Kim, Hyun Ji (BK21PLUS R-FIND Team, College of Pharmacy, Dongguk University)
Park, Mi Kyung (BK21PLUS R-FIND Team, College of Pharmacy, Dongguk University)
Kang, Gyeung Jin (BK21PLUS R-FIND Team, College of Pharmacy, Dongguk University)
Byun, Hyun Jung (BK21PLUS R-FIND Team, College of Pharmacy, Dongguk University)
Lee, Ho (National Cancer Center)
Lee, Chang Hoon (BK21PLUS R-FIND Team, College of Pharmacy, Dongguk University)
Publication Information
Biomolecules & Therapeutics / v.23, no.2, 2015 , pp. 141-148 More about this Journal
Abstract
Epithelial mesenchymal transition (EMT) is the first step in metastasis and implicated in the phenotype of cancer stem cells. Therefore, understanding and controlling EMT, are essential to the prevention and cure of metastasis. In the present study, we examined, by Western blot, reverse transcription polymerase chain reaction (RT-PCR), and confocal microscopy, the effects of cardamonin (CDN) on transforming growth factor-${\beta}1$ (TGF-${\beta}1$)-induced EMT of A549 lung adenocarcinoma cell lines. TGF-${\beta}1$ induced expression of N-cadherin and decreased expression of E-cadherin. CDN suppressed N-cadherin expression and restored E-cadherin expression. Further, TGF-${\beta}1$ induced migration and invasion of A549 cancer cells, which was suppressed by CDN. TGF-${\beta}1$ induced c-Jun N-terminal kinase (JNK) activation during EMT, but CDN blocked it. Protein serine/threonine phosphatase 2A (PP2A) expression in A549 cancer cells was reduced by TGF-${\beta}1$ but CDN restored it. The overall data suggested that CDN suppresses TGF-${\beta}1$-induced EMT via PP2A restoration, making it a potential new drug candidate that controls metastasis.
Keywords
Cardamonin; Epithelial mesenchymal transition; TGF-${\beta}1$; JNK; PP2A; A549;
Citations & Related Records
Times Cited By KSCI : 3  (Citation Analysis)
연도 인용수 순위
1 Ahmad, S., Israf, D. A., Lajis, N. H., Shaari, K., Mohamed, H., Wahab, A. A., Ariffin, K. T., Hoo, W. Y., Aziz, N. A., Kadir, A. A., Sulaiman, M. R. and Somchit, M. N. (2006) Cardamonin, inhibits pro-inflammatory mediators in activated RAW 264.7 cells and whole blood. Eur. J. Pharmacol. 538, 188-194.   DOI
2 Alcorn, J. F., Guala, A. S., van der Velden, J., McElhinney, B., Irvin, C. G., Davis, R. J. and Janssen-Heininger, Y. M. (2008) Jun Nterminal kinase 1 regulates epithelial-to-mesenchymal transition induced by TGF-beta1. J. Cell Sci. 121, 1036-1045.   DOI
3 Blick, T., Hugo, H., Widodo, E., Waltham, M., Pinto, C., Mani, S. A., Weinberg, R. A., Neve, R. M., Lenburg, M. E. and Thompson, E. W. (2010) Epithelial mesenchymal transition traits in human breast cancer cell lines parallel the CD44(hi/)CD24 (lo/-) stem cell phenotype in human breast cancer. J. Mammary Gland Biol. Neoplasia 15, 235-252.   DOI
4 Chow, Y. L., Lee, K. H., Vidyadaran, S., Lajis, N. H., Akhtar, M. N., Israf, D. A. and Syahida, A. (2012) Cardamonin from Alpinia rafflesiana inhibits inflammatory responses in IFN-gamma/LPS-stimulated BV2 microglia via NF-kappaB signalling pathway. Int. Immunopharmacol. 12, 657-665.   DOI
5 Davis, R. J. (2000) Signal transduction by the JNK group of MAP kinases. Cell 103, 239-252.   DOI
6 Denlinger, C. E., Ikonomidis, J. S., Reed, C. E. and Spinale, F. G. (2010) Epithelial to mesenchymal transition: the doorway to metastasis in human lung cancers. J. Thorac. Cardiovasc. Surg. 140, 505-513.   DOI
7 Fellner, T., Lackner, D. H., Hombauer, H., Piribauer, P., Mudrak, I., Zaragoza, K., Juno, C. and Ogris, E. (2003) A novel and essential mechanism determining specificity and activity of protein phosphatase 2A (PP2A) in vivo. Genes Dev. 17, 2138-2150.   DOI
8 Hatziieremia, S., Gray, A. I., Ferro, V. A., Paul, A. and Plevin, R. (2006) The effects of cardamonin on lipopolysaccharide-induced inflammatory protein production and MAP kinase and NFkappaB signalling pathways in monocytes/macrophages. Br. J. Pharmacol. 149, 188-198.
9 He, W., Jiang, Y., Zhang, X., Zhang, Y., Ji, H. and Zhang, N. (2014) Anticancer cardamonin analogs suppress the activation of NF-kappaB pathway in lung cancer cells. Mol. Cell. Biochem. 389, 25-33.   DOI
10 Huang, P. H., Wang, D., Chuang, H. C., Wei, S., Kulp, S. K. and Chen, C. S. (2009) alpha-Tocopheryl succinate and derivatives mediate the transcriptional repression of androgen receptor in prostate cancer cells by targeting the PP2A-JNK-Sp1-signaling axis. Carcinogenesis 30, 1125-1131.   DOI
11 Hung, J. J., Yang, M. H., Hsu, H. S., Hsu, W. H., Liu, J. S. and Wu, K. J. (2009) Prognostic significance of hypoxia-inducible factor-1alpha, TWIST1 and Snail expression in resectable non-small cell lung cancer. Thorax 64, 1082-1089.   DOI   ScienceOn
12 Ikushima, H. and Miyazono, K. (2010) TGFbeta signalling: a complex web in cancer progression. Nat. Rev. Cancer 10, 415-424.   DOI
13 Kalluri, R. and Weinberg, R. A. (2009) The basics of epithelial-mesenchymal transition. J. Clin. Invest. 119, 1420-1428.   DOI
14 Kawata, M., Koinuma, D., Ogami, T., Umezawa, K., Iwata, C., Watabe, T. and Miyazono, K. (2012) TGF-beta-induced epithelial-mesenchymal transition of A549 lung adenocarcinoma cells is enhanced by pro-inflammatory cytokines derived from RAW 264.7 macrophage cells. J. Biochem. 151, 205-216.   DOI
15 Kim, D. S., Park, S. S., Nam, B. H., Kim, I. H. and Kim, S. Y. (2006) Reversal of drug resistance in breast cancer cells by transglutaminase 2 inhibition and nuclear factor-kappaB inactivation. Cancer Res. 66, 10936-10943.   DOI
16 Li, H., Li, Y., Liu, D. and Liu, J. (2014) LPS promotes epithelial-mesenchymal transition and activation of TLR4/JNK signaling. Tumour Biol. 35, 10429-10435.   DOI
17 Kim, J. H., Jang, Y. S., Eom, K. S., Hwang, Y. I., Kang, H. R., Jang, S. H., Kim, C. H., Park, Y. B., Lee, M. G., Hyun, I. G., Jung, K. S. and Kim, D. G. (2007) Transforming growth factor beta1 induces epithelial-to-mesenchymal transition of A549 cells. J. Korean Med. Sci. 22, 898-904.   DOI
18 Kins, S., Kurosinski, P., Nitsch, R. M. and Gotz, J. (2003) Activation of the ERK and JNK signaling pathways caused by neuron-specific inhibition of PP2A in transgenic mice. Am. J. Pathol. 163, 833-843.   DOI
19 Lee, H. J., Park, M. K., Lee, E. J. and Lee, C. H. (2013) Resolvin D1 inhibits TGF-beta1-induced epithelial mesenchymal transition of A549 lung cancer cells via lipoxin A4 receptor/formyl peptide receptor 2 and GPR32. Int. J. Biochem. Cell Biol. 45, 2801-2807.   DOI
20 McConnell, J. L., Watkins, G. R., Soss, S. E., Franz, H. S., McCorvey, L. R., Spiller, B. W., Chazin, W. J. and Wadzinski, B. E. (2010) Alpha4 is a ubiquitin-binding protein that regulates protein serine/threonine phosphatase 2A ubiquitination. Biochemistry 49, 1713-1718.   DOI
21 Neviani, P. and Perrotti, D. (2014) SETting OP449 into the PP2A-activating drug family. Clin. Cancer Res. 20, 2026-2028.   DOI
22 Park, M. K., Cho, S. A., Lee, H. J., Lee, E. J., Kang, J. H., Kim, Y. L., Kim, H. J., Oh, S. H., Choi, C., Lee, H. and Kim, S. Y. (2012) Suppression of transglutaminase-2 is involved in anti-inflammatory actions of glucosamine in 12-O-tetradecanoylphorbol-13-acetateinduced skin inflammation. Biomol. Ther. 20, 380-385.   DOI
23 Park, M. K., You, H. J., Lee, H. J., Kang, J. H., Oh, S. H., Kim, S. Y. and Lee, C. H. (2013b) Transglutaminase-2 induces N-cadherin expression in TGF-beta1-induced epithelial mesenchymal transition via c-Jun-N-terminal kinase activation by protein phosphatase 2A down-regulation. Eur. J. Cancer 49, 1692-1705.   DOI   ScienceOn
24 Park, M. K., Choi, J. K., Kim, H. J., Nakahata, N., Lim, K. M., Kim, S. Y. and Lee, C. H. (2014a) Novel inhibitory effects of cardamonin on thromboxane A-induced scratching response: Blocking of G/transglutaminase- 2 binding to thromboxane A receptor. Pharmacol. Biochem. Behav. 126C, 131-135.
25 Park, M. K., Jo, S. H., Lee, H. J., Kang, J. H., Kim, Y. R., Kim, H. J., Lee, E. J., Koh, J. Y., Ahn, K. O., Jung, K. C., Oh, S. H., Kim, S. Y. and Lee, C. H. (2013a) Novel suppressive effects of cardamonin on the activity and expression of transglutaminase-2 lead to blocking the migration and invasion of cancer cells. Life Sci. 92, 154-160.   DOI   ScienceOn
26 Park, M. K., Lee, H. J., Choi, J. K., Kim, H. J., Kang, J. H., Lee, E. J., Kim, Y. R., Kang, J. H., Yoo, J. K., Cho, H. Y., Kim, J. K., Kim, C. H., Park, J. H. and Lee, C. H. (2014b) Novel anti-nociceptive effects of cardamonin via blocking expression of cyclooxygenase-2 and transglutaminase-2. Pharmacol. Biochem. Behav. 118, 10-15.   DOI
27 Park, S., Gwak, J., Han, S. J. and Oh, S. (2013c) Cardamonin suppresses the proliferation of colon cancer cells by promoting betacatenin degradation. Biol. Pharm. Bull. 36, 1040-1044.   DOI   ScienceOn
28 Parkin, D. M., Bray, F., Ferlay, J. and Pisani, P. (2005) Global cancer statistics, 2002. CA Cancer J. Clin. 55, 74-108.   DOI
29 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
30 Prudkin, L., Liu, D. D., Ozburn, N. C., Sun, M., Behrens, C., Tang, X., Brown, K. C., Bekele, B. N., Moran, C. and Wistuba, I. I. (2009) Epithelial-to-mesenchymal transition in the development and progression of adenocarcinoma and squamous cell carcinoma of the lung. Mod. Pathol. 22, 668-678.   DOI
31 Ryoo, I. G., Shin, D. H., Kang, K. S. and Kwak, M. K. (2014) Involvement of Nrf2-GSH signaling in TGFbeta1-stimulated epithelial-to-mesenchymal transition changes in rat renal tubular cells. Arch. Pharm. Res. 10.1007/s12272-014-0380-y [Epub ahead of print]   DOI
32 Saddoughi, S. A., Gencer, S., Peterson, Y. K., Ward, K. E., Mukhopadhyay, A., Oaks, J., Bielawski, J., Szulc, Z. M., Thomas, R. J., Selvam, S. P., Senkal, C. E., Garrett-Mayer, E., De Palma, R. M., Fedarovich, D., Liu, A., Habib, A. A., Stahelin, R. V., Perrotti, D. and Ogretmen, B. (2013) Sphingosine analogue drug FTY720 targets I2PP2A/SET and mediates lung tumour suppression via activation of PP2A-RIPK1-dependent necroptosis. EMBO Mol. Med. 5, 105-121.   DOI
33 Sheen, Y. Y., Kim, M. J., Park, S. A., Park, S. Y. and Nam, J. S. (2013) Targeting the transforming growth factor-beta signaling in cancer therapy. Biomol. Ther. 21, 323-331.   DOI
34 Switzer, C. H., Ridnour, L. A., Cheng, R. Y., Sparatore, A., Del Soldato, P., Moody, T. W., Vitek, M. P., Roberts, D. D. and Wink, D. A. (2009) Dithiolethione compounds inhibit Akt signaling in human breast and lung cancer cells by increasing PP2A activity. Oncogene 28, 3837-3846.   DOI
35 Tang, Y., Fang, Q., Shi, D., Niu, P., Chen, Y. and Deng, J. (2014) mTOR inhibition of cardamonin on antiproliferation of A549 cells is involved in a FKBP12 independent fashion. Life Sci. 99, 44-51.   DOI
36 Williams, B. A., Sugimura, H., Endo, C., Nichols, F. C., Cassivi, S. D., Allen, M. S., Pairolero, P. C., Deschamps, C. and Yang, P. (2006) Predicting postrecurrence survival among completely resected nonsmall-cell lung cancer patients. Ann. Thorac. Surg. 81, 1021-1027.   DOI
37 Velden, J. L., Alcorn, J. F., Guala, A. S., Badura, E. C. and Janssen-Heininger, Y. M. (2011) c-Jun N-terminal kinase 1 promotes transforming growth factor-beta1-induced epithelial-to-mesenchymal transition via control of linker phosphorylation and transcriptional activity of Smad3. Am. J. Respir. Cell Mol. Biol. 44, 571-581.   DOI
38 Wang, J., Kuiatse, I., Lee, A. V., Pan, J., Giuliano, A. and Cui, X. (2010) Sustained c-Jun-NH2-kinase activity promotes epithelialmesenchymal transition, invasion, and survival of breast cancer cells by regulating extracellular signal-regulated kinase activation. Mol.Cancer Res. 8, 266-277.   DOI
39 Wang, S., Zhou, L., He, W. and Hu, Z. (2007) Separation and determination of alpinetin and cardamonin by reverse micelle electrokinetic capillary chromatography. J. Pharm. Biomed. Anal. 43, 1557-1561.   DOI
40 Yadav, V. R., Prasad, S. and Aggarwal, B. B. (2012) Cardamonin sensitizes tumour cells to TRAIL through ROS- and CHOP-mediated up-regulation of death receptors and down-regulation of survival proteins. Br. J. Pharmacol. 165, 741-753.   DOI
41 Yamashita, M., Fatyol, K., Jin, C., Wang, X., Liu, Z. and Zhang, Y. E. (2008) TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-beta. Mol. Cell 31, 918-924.   DOI