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http://dx.doi.org/10.5808/gi.21041

2-Methoxy-1,4-naphthoquinone (MNQ) regulates cancer key genes of MAPK, PI3K, and NF-κB pathways in Raji cells  

Wong, Teck Yew (Centre for Cancer Research, Universiti Tunku Abdul Rahman)
Menaga, Subramaniam (Centre for Cancer Research, Universiti Tunku Abdul Rahman)
Huang, Chi-Ying F. (Institute of Biopharmaceutical Sciences, National Yang-Ming University)
Ho, Siong Hock Anthony (School of Biosciences, Taylor's University, Lakeside Campus 1)
Gan, Seng Chiew (Department of Pre-Clinical Sciences Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman)
Lim, Yang Mooi (Centre for Cancer Research, Universiti Tunku Abdul Rahman)
Abstract
2-Methoxy-1,4-naphthoquinone (MNQ) has been shown to cause cytotoxic towards various cancer cell lines. This study is designed to investigate the regulatory effect of MNQ on the key cancer genes in mitogen-activated protein kinase, phosphoinositide 3-kinase, and nuclear factor κB signaling pathways. The expression levels of the genes were compared at different time point using polymerase chain reaction arrays and Ingenuity Pathway Analysis was performed to identify gene networks that are most significant to key cancer genes. A total of 43 differentially expressed genes were identified with 21 up-regulated and 22 down-regulated genes. Up-regulated genes were involved in apoptosis, cell cycle and act as tumor suppressor while down-regulated genes were involved in anti-apoptosis, angiogenesis, cell cycle and act as transcription factor as well as proto-oncogenes. MNQ exhibited multiple regulatory effects on the cancer key genes that targeting at cell proliferation, cell differentiation, cell transformation, apoptosis, reduce inflammatory responses, inhibits angiogenesis and metastasis.
Keywords
2-methoxy-1,4-naphthoquinone; cancer chemoprevention; MAPK pathway; nuclear factor-kappa B pathway; PI3K pathway;
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1 McDermott U, Ames RY, Iafrate AJ, Maheswaran S, Stubbs H, Greninger P, et al. Ligand-dependent platelet-derived growth factor receptor (PDGFR)-alpha activation sensitizes rare lung cancer and sarcoma cells to PDGFR kinase inhibitors. Cancer Res 2009;69:3937-3946.   DOI
2 Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 2009;8:627-644.   DOI
3 Ong JY, Yong PV, Lim YM, Ho AS. 2-Methoxy-1,4-naphthoquinone (MNQ) induces apoptosis of A549 lung adenocarcinoma cells via oxidation-triggered JNK and p38 MAPK signaling pathways. Life Sci 2015;135:158-164.   DOI
4 Gallagher EJ, LeRoith D. Diabetes, cancer, and metformin: connections of metabolism and cell proliferation. Ann N Y Acad Sci 2011;1243:54-68.   DOI
5 Aggarwal BB. Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 2003;3:745-756.   DOI
6 Miura A, Honma R, Togashi T, Yanagisawa Y, Ito E, Imai J, et al. Differential responses of normal human coronary artery endothelial cells against multiple cytokines comparatively assessed by gene expression profiles. FEBS Lett 2006;580:6871-6879.   DOI
7 Bender LM, Morgan MJ, Thomas LR, Liu ZG, Thorburn A. The adaptor protein TRADD activates distinct mechanisms of apoptosis from the nucleus and the cytoplasm. Cell Death Differ 2005;12:473-481.   DOI
8 Gong Y, Scott E, Lu R, Xu Y, Oh WK, Yu Q. TIMP-1 promotes accumulation of cancer associated fibroblasts and cancer progression. PLoS One 2013;8:e77366.   DOI
9 Maldonado V, Espinosa M, Pruefer F, Patino N, Ceballos-Canciono G, Urzua U, et al. Gene regulation by BCL3 in a cervical cancer cell line. Folia Biol (Praha) 2010;56:183-193.
10 Rak J, Yu JL. Oncogenes and tumor angiogenesis: the question of vascular "supply" and vascular "demand". Semin Cancer Biol 2004;14:93-104.   DOI
11 Laubenbacher R, Hower V, Jarrah A, Torti SV, Shulaev V, Mendes P, et al. A systems biology view of cancer. Biochim Biophys Acta 2009;1796:129-139.
12 Nakanishi M, Shimada M, Niida H. Genetic instability in cancer cells by impaired cell cycle checkpoints. Cancer Sci 2006;97:984-989.   DOI
13 Croce CM. Oncogenes and cancer. N Engl J Med 2008;358:502-511.   DOI
14 Gordon K, Clouaire T, Bao XX, Kemp SE, Xenophontos M, de Las Heras JI, et al. Immortality, but not oncogenic transformation, of primary human cells leads to epigenetic reprogramming of DNA methylation and gene expression. Nucleic Acids Res 2014;42:3529-3541.   DOI
15 Wang LH, Wu CF, Rajasekaran N, Shin YK. Loss of tumor suppressor gene function in human cancer: an overview. Cell Physiol Biochem 2018;51:2647-2693.   DOI
16 Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646-674.   DOI
17 Han Y. Analysis of the role of the Hippo pathway in cancer. J Transl Med 2019;17:116.   DOI
18 Elliott SF, Coon CI, Hays E, Stadheim TA, Vincenti MP. Bcl-3 is an interleukin-1-responsive gene in chondrocytes and synovial fibroblasts that activates transcription of the matrix metalloproteinase 1 gene. Arthritis Rheum 2002;46:3230-3239.   DOI
19 Kuwata H, Watanabe Y, Miyoshi H, Yamamoto M, Kaisho T, Takeda K, et al. IL-10-inducible Bcl-3 negatively regulates LPS-induced TNF-alpha production in macrophages. Blood 2003;102:4123-4129.   DOI
20 Pelullo M, Zema S, Nardozza F, Checquolo S, Screpanti I, Bellavia D. Wnt, Notch, and TGF-beta pathways impinge on Hedgehog signaling complexity: an open window on cancer. Front Genet 2019;10:711.   DOI
21 Khazaei S, Esa NM, Ramachandran V, Hamid RA, Pandurangan AK, Etemad A, et al. In vitro antiproliferative and apoptosis inducing effect of Allium atroviolaceum Bulb extract on breast, cervical, and liver cancer cells. Front Pharmacol 2017;8:5.   DOI
22 Zhang X, Tang N, Hadden TJ, Rishi AK. Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta 2011;1813:1978-1986.   DOI
23 Daughaday WH, Hall K, Raben MS, Salmon WD Jr, van den Brande JL, van Wyk JJ. Somatomedin: proposed designation for sulphation factor. Nature 1972;235:107.   DOI
24 Arnaldez FI, Helman LJ. Targeting the insulin growth factor receptor 1. Hematol Oncol Clin North Am 2012;26:527-542.   DOI
25 Vatsveen TK, Ro TB, Hella H, et al. High expression of BCL3 in human myeloma cells is associated with increased proliferation and inferior prognosis. Eur J Haematol 2009;82:354-363.   DOI
26 Hu X, Nesic-Taylor O, Qiu J, Rea HC, Fabian R, Rassin DK, et al. Activation of nuclear factor-kappaB signaling pathway by interleukin-1 after hypoxia/ischemia in neonatal rat hippocampus and cortex. J Neurochem 2005;93:26-37.   DOI
27 Rocha S, Martin AM, Meek DW, Perkins ND. p53 represses cyclin D1 transcription through down regulation of Bcl-3 and inducing increased association of the p52 NF-kappaB subunit with histone deacetylase 1. Mol Cell Biol 2003;23:4713-4727.   DOI
28 Wurtz SO, Schrohl AS, Mouridsen H, Brunner N. TIMP-1 as a tumor marker in breast cancer: an update. Acta Oncol 2008;47:580-590.
29 Valenzuela JO, Hammerbeck CD, Mescher MF. Cutting edge: Bcl-3 up-regulation by signal 3 cytokine (IL-12) prolongs survival of antigen-activated CD8 T cells. J Immunol 2005;174:600-604.   DOI
30 Brocke-Heidrich K, Ge B, Cvijic H, Pfeifer G, Loffler D, Henze C, et al. BCL3 is induced by IL-6 via Stat3 binding to intronic enhancer HS4 and represses its own transcription. Oncogene 2006;25:7297-7304.   DOI
31 Folco EJ, Rocha VZ, Lopez-Ilasaca M, Libby P. Adiponectin inhibits pro-inflammatory signaling in human macrophages independent of interleukin-10. J Biol Chem 2009;284:25569-25575.   DOI
32 Raab-Traub N. Epstein-Barr virus LMP1 activates EGFR, STAT3, and ERK through effects on PKCdelta. J Virol 2011;85:4399-4408.   DOI
33 MacEwan DJ. TNF receptor subtype signalling: differences and cellular consequences. Cell Signal 2002;14:477-492.   DOI
34 Liew K, Yong PV, Lim YM, Navaratnam V, Ho AS. 2-Methoxy-1,4-Naphthoquinone (MNQ) suppresses the invasion and migration of a human metastatic breast cancer cell line (MDAMB-231). Toxicol In Vitro 2014;28:335-339.   DOI
35 Hemmings BA, Restuccia DF. PI3K-PKB/Akt pathway. Cold Spring Harb Perspect Biol 2012;4:a011189.   DOI
36 Heissmeyer V, Krappmann D, Wulczyn FG, Scheidereit C. NF-kappaB p105 is a target of IkappaB kinases and controls signal induction of Bcl-3-p50 complexes. EMBO J 1999;18:4766-4778.   DOI
37 Etienne-Manneville S. APC in cell migration. Adv Exp Med Biol 2009;656:30-40.   DOI
38 McKinsey EL, Parrish JK, Irwin AE, Niemeyer BF, Kern HB, Birks DK, et al. A novel oncogenic mechanism in Ewing sarcoma involving IGF pathway targeting by EWS/Fli1-regulated microRNAs. Oncogene 2011;30:4910-4920.   DOI
39 D'Osualdo A, Ferlito F, Prigione I, Obici L, Meini A, Zulian F, et al. Neutrophils from patients with TNFRSF1A mutations display resistance to tumor necrosis factor-induced apoptosis: pathogenetic and clinical implications. Arthritis Rheum 2006;54:998-1008.   DOI
40 Lee RU, Saland S, Sullivan S. Tumor necrosis factor receptor-associated periodic syndrome as a cause of recurrent abdominal pain in identical twins and description of a novel mutation of the TNFRSF1A gene. J Pediatr Gastroenterol Nutr 2013;56:e22-23.   DOI
41 Ding ZS, Jiang FS, Chen NP, Lv GY, Zhu CG. Isolation and identification of an anti-tumor component from leaves of Impatiens balsamina. Molecules 2008;13:220-229.   DOI
42 Schulz WA. Molecular Biology of Human Cancers: An Advanced Student's Textbook. Dordrecht: Springer, 2007. pp. 113-144.
43 Gajate C, Mollinedo F. Cytoskeleton-mediated death receptor and ligand concentration in lipid rafts forms apoptosis-promoting clusters in cancer chemotherapy. J Biol Chem 2005;280:11641-11647.   DOI
44 Berridge KC, Robinson TE, Aldridge JW. Dissecting components of reward: 'liking', 'wanting', and learning. Curr Opin Pharmacol 2009;9:65-73.   DOI
45 Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 2009;9:550-562.   DOI
46 Gao SP, Mark KG, Leslie K, Pao W, Motoi N, Gerald WL, et al. Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J Clin Invest 2007;117:3846-3856.   DOI
47 Guo Y, Xu F, Lu T, Duan Z, Zhang Z. Interleukin-6 signaling pathway in targeted therapy for cancer. Cancer Treat Rev 2012;38:904-910.   DOI
48 Wakefield A, Soukupova J, Montagne A, Ranger J, French R, Muller WJ, et al. Bcl3 selectively promotes metastasis of ERBB2-driven mammary tumors. Cancer Res 2013;73:745-755.
49 Rebollo A, Dumoutier L, Renauld JC, Zaballos A, Ayllon V, Martinez AC. Bcl-3 expression promotes cell survival following interleukin-4 deprivation and is controlled by AP1 and AP1-like transcription factors. Mol Cell Biol 2000;20:3407-3416.   DOI
50 Teng O. Isolation and characterisation of a cytotoxic napthoquinone from Impatiens balsamina. M.S. thesis. Kampar: Universiti Tunku Abdul Rahman, 2010.
51 Yew WT, Kitson L, Hock AH, Chiew GS, Mooi LY. 2-Methoxy-1,4-naphthoquinone (MNQ) suppresses protein kinase C βI, δ, and ζ expression in Raji cells. J Appl Pharm Sci 2015;5:001-005.
52 Tan SY. Differential protein expression in K562 following exposure to MNQ isolated from Impatiens balsamina, Linn. M.S. thesis. Kampar: Universiti Tunku Abdul Rahman, 2011.
53 Mori N, Toume K, Arai MA, Koyano T, Kowithayakorn T, Ishibashi M. 2-methoxy-1,4-naphthoquinone isolated from Impatiens balsamina in a screening program for activity to inhibit Wnt signaling. J Nat Med 2011;65:234-236.   DOI
54 Liew K, Yong PV, Navaratnam V, Lim YM, Ho AS. Differential proteomic analysis on the effects of 2-methoxy-1,4-naphthoquinone towards MDA-MB-231 cell line. Phytomedicine 2015;22:517-527.   DOI
55 Bell HS, Ryan KM. Intracellular signalling and cancer: complex pathways lead to multiple targets. Eur J Cancer 2005;41:206-215.   DOI
56 Song J, Zhang J, Wang J, Cao Z, Wang J, Guo X, et al. beta1 integrin modulates tumor growth and apoptosis of human colorectal cancer. Oncol Rep 2014;32:302-308.   DOI