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http://dx.doi.org/10.9721/KJFST.2018.50.1.105

Melittin inhibits cell migration and invasion via blocking of the epithelial-mesenchymal transition (EMT) in lung cancer cells  

Cho, Hyun-Ji (Research Institute of Biomedical Engineering)
Jeong, Yun-Jeong (Research Institute of Biomedical Engineering)
Kim, Mun-Hyeon (Research Institute of Biomedical Engineering)
Chung, Il-Kyung (Department of Biotechnology, Catholic University of Daegu)
Kang, Dong Wook (Department of pharmaceutical science and technology, Catholic University of Daegu)
Chang, Young-Chae (Research Institute of Biomedical Engineering)
Publication Information
Korean Journal of Food Science and Technology / v.50, no.1, 2018 , pp. 105-110 More about this Journal
Abstract
Melittin is the main component of apitoxin (bee venom) that has been reported to have anti-inflammatory and anti-cancer effects. Herein, we demonstrated that inhibition of epithelial-mesenchymal transition (EMT) by melittin causes suppression of cancer cell migration and invasion. Melittin significantly suppressed the epidermal growth factor (EGF)-induced cell migration and invasion in lung cancer cells. Moreover, melittin up-regulated the expression of epithelial marker protein, E-cadherin, and down-regulated the expression of EMT related proteins, vimentin and fibronectin. Mechanistic studies revealed that melittin markedly suppressed the expression of EMT mediated transcription factors, ZEB2, Slug, and Snail. The EGF-induced phosphorylation of AKT, mTOR, P70S6K, and 4EBP1 was also inhibited by melittin, but not that of ERK and JNK. Therefore, the inhibitory effect of melittin on migration and invasion of lung cancer cells may be associated with the inhibition of EMT via blocking of the AKT-mTOR-P70S6K-4EBP1 pathway.
Keywords
melittin; epithelial-mesenchymal transition (EMT); migration; invasion; lung cancer;
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1 Derksen PW, Liu X, Saridin F, van der Gulden H, Zevenhoven J, Evers B, van Beijnum JR, Griffioen AW, Vink J, Krimpenfort P, Peterse JL, Cardiff RD, Berns A, Jonkers J. Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis. Cancer Cell 10: 437-449 (2006)   DOI
2 Zhang C, Liu T, Wang G, Wang H, Che X, Gao X, Liu H. Rac3 regulates cell invasion, migration and EMT in lung adenocarcinoma through p38 MAPK pathway. J. Cancer 8: 2511-2522 (2017)   DOI
3 Liu XL, Zhang XT, Meng J, Zhang HF, Zhao Y, Li C, Sun Y, Mei QB, Zhang F, Zhang T. ING5 knockdown enhances migration and invasion of lung cancer cells by inducing EMT via EGFR/PI3K/Akt and IL-6/STAT3 signaling pathways. Oncotarget 8: 54265-54276 (2017)
4 Billingham ME, Morley J, Hanson JM, Shipolini RA, Vernon CA. Letter: An anti-inflammatory peptide from bee venom. Nature 245: 163-164 (1973)   DOI
5 Yu HY, Liu MG, Liu DN, Shang GW, Wang Y, Qi C, Zhang KP, Song ZJ, Chen J. Antinociceptive effects of systemic paeoniflorin on bee venom-induced various 'phenotypes' of nociception and hypersensitivity. Pharmacol. Biochem. Behav. 88: 131-140 (2007)   DOI
6 Moon DO, Park SY, Lee KJ, Heo MS, Kim KC, Kim MO, Lee JD, Choi YH, Kim GY. Bee venom and melittin reduce proinflammatory mediators in lipopolysaccharide-stimulated BV2 microglia. Int. Immunopharmacol. 7: 1092-1101 (2007)   DOI
7 Park SH, Cho HJ, Jeong YJ, Shin JM, Kang JH, Park KK, Choe JY, Park YY, Bae YS, Han SM, Moon SK, Kim WJ, Choi YH, Chang YC. Melittin inhibits TGF-beta-induced pro-fibrotic gene expression through the suppression of the TGFbetaRII-Smad, ERK1/2 and JNK-mediated signaling pathway. Am. J. Chin. Med. 42: 1139-1152 (2014)   DOI
8 Park JH, Lee WR, Kim HS, Han SM, Chang YC, Park KK. Protective effects of melittin on tumor necrosis factor-alpha induced hepatic damage through suppression of apoptotic pathway and nuclear factor-kappa B activation. Exp. Biol. Med. (Maywood) 239: 1705-1714 (2014)   DOI
9 Jeong YJ, Shin JM, Bae YS, Cho HJ, Park KK, Choe JY, Han SM, Moon SK, Kim WJ, Choi YH, Kim CH, Chang HW, Chang YC. Melittin has a chondroprotective effect by inhibiting MMP-1 and MMP-8 expressions via blocking NF-kappaB and AP-1 signaling pathway in chondrocytes. Int. Immunopharmacol. 25: 400-405 (2015)   DOI
10 Park JH, Jeong YJ, Park KK, Cho HJ, Chung IK, Min KS, Kim M, Lee KG, Yeo JH, Park KK, Chang YC. Melittin suppresses PMA-induced tumor cell invasion by inhibiting NF-kappaB and AP-1-dependent MMP-9 expression. Mol. Cells 29: 209-215 (2010)   DOI
11 Manupati K, Dhoke NR, Debnath T, Yeeravalli R, Guguloth K, Saeidpour S, De UC, Debnath S, Das A. Inhibiting epidermal growth factor receptor signalling potentiates mesenchymal-epithelial transition of breast cancer stem cells and their responsiveness to anticancer drugs. FEBS J. 284: 1830-1854 (2017)   DOI
12 Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J, Garcia De Herreros A. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat. Cell Biol. 2: 84-89 (2000)   DOI
13 Han B, Cui H, Kang L, Zhang X, Jin Z, Lu L, Fan Z. Metformin inhibits thyroid cancer cell growth, migration, and EMT through the mTOR pathway. Tumour. Biol. 36: 6295-6304 (2015)   DOI
14 Bolos V, Peinado H, Perez-Moreno MA, Fraga MF, Esteller M, Cano A. The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors. J. Cell Sci. 116: 499-511 (2003)   DOI
15 Sanchez-Tillo E, Lazaro A, Torrent R, Cuatrecasas M, Vaquero EC, Castells A, Engel P, Postigo A. ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SNF chromatinremodeling protein BRG1. Oncogene 29: 3490-3500 (2010)   DOI
16 Pei Z, Fu W, Wang G. A natural product toosendanin inhibits epithelial-mesenchymal transition and tumor growth in pancreatic cancer via deactivating Akt/mTOR signaling. Biochem. Biophys. Res. Commun. 493: 455-460 (2017)   DOI
17 Xu M, Qin S, Cao F, Ding S, Li M. MicroRNA-379 inhibits metastasis and epithelial-mesenchymal transition via targeting FAK/AKT signaling in gastric cancer. Int. J. Oncol. 51: 867-876 (2017)   DOI
18 Cicchini C, Laudadio I, Citarella F, Corazzari M, Steindler C, Conigliaro A, Fantoni A, Amicone L, Tripodi M. TGFbeta-induced EMT requires focal adhesion kinase (FAK) signaling. Exp. Cell Res. 314: 143-152 (2008)   DOI
19 Gonzalez DM, Medici D. Signaling mechanisms of the epithelialmesenchymal transition. Sci. Signal. 7: re8 (2014)   DOI
20 Bailey KM, Liu J. Caveolin-1 up-regulation during epithelial to mesenchymal transition is mediated by focal adhesion kinase. J. Biol. Chem. 283: 13714-13724 (2008)   DOI
21 Heerboth S, Housman G, Leary M, Longacre M, Byler S, Lapinska K, Willbanks A, Sarkar S. EMT and tumor metastasis. Clin. Transl. Med. 4: 6 (2015)   DOI
22 Jeong YJ, Choi Y, Shin JM, Cho HJ, Kang JH, Park KK, Choe JY, Bae YS, Han SM, Kim CH, Chang HW, Chang YC. Melittin suppresses EGF-induced cell motility and invasion by inhibiting PI3K/Akt/mTOR signaling pathway in breast cancer cells. Food Chem. Toxicol. 68: 218-225 (2014)   DOI
23 Yun Y, Gao R, Yue H, Guo L, Li G, Sang N. Sulfate aerosols promote lung cancer metastasis by epigenetically regulating the epithelial-to-mesenchymal transition (EMT). Environ. Sci. Technol. 51: 11401-11411 (2017)   DOI
24 Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat. Rev. Mol. Cell Biol. 15: 178-196 (2014)   DOI
25 Kinugawa K, Minobe WA, Wood WM, Ridgway EC, Baxter JD, Ribeiro RC, Tawadrous MF, Lowes BA, Long CS, Bristow MR. Signaling pathways responsible for fetal gene induction in the failing human heart: evidence for altered thyroid hormone receptor gene expression. Circulation 103: 1089-1094 (2001)   DOI