Determination of Usnic Acid Responsive miRNAs in Breast Cancer Cell Lines

Author(s): Nil Kiliç, Yasemin Ö. Islakoğlu, İlker Büyük, Bala Gür-Dedeoğlu, Demet Cansaran-Duman*

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 19 , Issue 12 , 2019

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Graphical Abstract:


Abstract:

Objective: Breast Cancer (BC) is the most common type of cancer diagnosed in women. A common treatment strategy for BC is still not available because of its molecular heterogeneity and resistance is developed in most of the patients through the course of treatment. Therefore, alternative medicine resources as being novel treatment options are needed to be used for the treatment of BC. Usnic Acid (UA) that is one of the secondary metabolites of lichens used for different purposes in the field of medicine and its anti-proliferative effect has been shown in certain cancer types, suggesting its potential use for the treatment.

Methods: Anti-proliferative effect of UA in BC cells (MDA-MB-231, MCF-7, BT-474) was identified through MTT analysis. Microarray analysis was performed in cells treated with the effective concentration of UA and UA-responsive miRNAs were detected. Their targets and the pathways that they involve were determined using a miRNA target prediction tool.

Results: Microarray experiments showed that 67 miRNAs were specifically responsive to UA in MDA-MB-231 cells while 15 and 8 were specific to BT-474 and MCF-7 cells, respectively. The miRNA targets were mostly found to play role in Hedgehog signaling pathway. TGF-Beta, MAPK and apoptosis pathways were also the prominent ones according to the miRNA enrichment analysis.

Conclusion: The current study is important as being the first study in the literature which aimed to explore the UA related miRNAs, their targets and molecular pathways that may have roles in the BC. The results of pathway enrichment analysis and anti-proliferative effects of UA support the idea that UA might be used as a potential alternative therapeutic agent for BC treatment.

Keywords: microRNA, breast cancer, usnic acid, microarray, anti-proliferative effect, alternative therapeutic agent.

[1]
Menyhart, O.; Santarpia, L.; Gyorffy, B. A comprehensive outline of trastuzumab resistance biomarkers in HER2 overexpressing breast cancer. Curr. Cancer Drug Targets, 2015, 15(8), 665-683.
[2]
Dias, D.A.; Urban, S.; Roessner, U. A historical overview of natural products in drug discovery. Metabolites, 2012, 2(2), 303-336.
[3]
Shrestha, G.; St., Clair; L.L., Lichens A promising source of antibiotic and anticancer drugs. Phytochem. Rev., 2013, 12(1), 229-244.
[4]
Ranković, B.; Kosanić, M.; Manojlović, N.; Rančić, A.; Stanojković, T. Chemical composition of hypogymnia physodes lichen and biological activities of some its major metabolites. Med. Chem. Res., 2014, 23(1), 408-416.
[5]
Ristić, S.; Ranković, B.; Kosanić, M.; Stanojković, T.; Stamenković, S.; Vasiljević, P.; Manojlović, I.; Manojlović, N. Phytochemical study and antioxidant, antimicrobial and anticancer activities of Melanelia subaurifera and Melanelia fuliginosa lichens. J. Food Sci. Technol., 2016, 53(6), 2804-2816.
[6]
Ristic, S.; Rankovic, B.; Kosanić, M.; Stamenkovic, S.; Stanojković, T.; Sovrlić, M.; Manojlović, N. Biopharmaceutical potential of two ramalina lichens and their metabolites. Curr. Pharm. Biotechnol., 2016, 17(7), 651-658.
[7]
Stanojkovi, T. Investigations of lichen secondary metabolites with potential anticancer activity. In: Lichen Secondary Metabolites: Bioactive Properties and Pharmaceutical Potential;; Branislav Ranković; Springer: Switzerland,. , 2015; pp. 127-146.
[8]
Koçer, S.; Uruş, S.; Çakır, A.; Güllüce, M.; Dığrak, M.; Alan, Y.; Aslan, A.; Tümer, M.; Karaday, M.; Kazaz, C.; Dal, H. The synthesis, characterization, antimicrobial and antimutagenic activities of hydroxyphenylimino ligands and their metal complexes of usnic acid isolated from Usnea longissima. Dalton Trans., 2014, 43(16), 6148-6164.
[9]
Zugic, A.; Jeremic, I.; Isakovic, A.; Arsic, I.; Savic, S.; Tadic, V. Evaluation of anticancer and antioxidant activity of a commercially available CO2 supercritical extract of old man’s beard (Usnea Barbata). PLoS One, 2016, 11(1)e0146342
[10]
Manojlović, N.; Ranković, B.; Kosanić, M.; Vasiljević, P.; Stanojković, T. Chemical composition of three parmelia lichens and antioxidant, antimicrobial and cytotoxic activities of some their major metabolites. Phytomedicine, 2012, 19(13), 1166-1172.
[11]
Zakharenko, A.; Luzina, O.; Koval, O.; Nilov, D.; Gushchina, I.; Dyrkheeva, N.; Švedas, V.; Salakhutdinov, N.; Lavrik, O. Tyrosyl-DNA phosphodiesterase 1 inhibitors: Usnic acid enamines enhance the cytotoxic effect of camptothecin. J. Nat. Prod., 2016, 79(11), 2961-2967.
[12]
Nguyen, T.T.; Yoon, S.; Yang, Y.; Lee, H.B.; Oh, S.; Jeong, M.H.; Kim, J.J.; Yee, S.T.; Crişan, F.; Moon, C.; Lee, K.Y. Lichen secondary metabolites in Flavocetraria cucullata exhibit anti-cancer effects on human cancer cells through the induction of apoptosis and suppression of tumorigenic potentials. PLoS One, 2014, 9(10)111575
[13]
Dinçsoy, A.B.; Duman, C.D. Changes in apoptosis-related gene expression profiles in cancer cell lines exposed to usnic acid lichen secondary metabolite. Turk. J. Biol., 2017, 41(3), 484-493.
[14]
Eryilmaz, I.E.; Eskiler, G.G.; Egeli, U.; Yurdacan, B.; Çeçener, G.; Tunca, B. In vitro cytotoxic and antiproliferative effects of usnic acid on hormone-dependent breast and prostate cancer cells. Biochem. Mol. Toxicol, 2018, 32(10)e22208
[15]
Song, Y.; Dai, F.; Zhai, D.; Dong, Y.; Zhang, J.; Lu, B.; Luo, J.; Liu, M.; Yi, Z. Usnic acid inhibits breast tumor angiogenesis and growth by suppressing VEGFR2-mediated AKT and ERK1/2 signaling pathways. Angiogenesis, 2012, 15, 421-432.
[16]
Kim, K.K.; Hur, J.S. Anticancer Activity of Lichen Metabolites and Their Mechanisms at the Molecular Level. In: Recent Advances in Lichenology: Modern Methods and Approaches in Lichen Systematics and Culture Techniques, Volume 2;; Upreti, D.K.; Divakar, P.K.; Shukla, V.; Bajpai, R.; Springer: Switzerland,. , 2015; pp. 201-208.
[17]
Iorio, M.V.; Croce, C.M. microRNA involvement in human cancer. Carcinogenesis, 2012, 33(6), 1126-1133.
[18]
Pinweha, P.; Rattanapornsompong, K.; Charoensawan, V.; Jitrapakdee, S. MicroRNAs and oncogenic transcriptional regulatory networks controlling metabolic reprogramming in cancers. Comput. Struct. Biotechnol. J., 2016, 14, 223-233.
[19]
Shivapurkar, N.; Vietsch, E.E.; Carney, E.; Isaacs, C.; Wellstein, A. Circulating microRNAs in patients with hormone receptor-positive, metastatic breast cancer treated with dovitinib. Clin. Transl. Med., 2017, 6(1), 37.
[20]
Boo, L.; Ho, W.Y.; Mohd Ali, N.; Yeap, S.K.; Ky, H.; Chan, K.G.; Yin, W.F.; Satharasinghe, D.A.; Liew, W.C.; Tan, S.W.; Cheong, S.K. Phenotypic and microRNA transcriptomic profiling of the MDA-MB-231 spheroid-enriched CSCs with comparison of MCF-7 microRNA profiling dataset. PeerJ, 2017, 5e3551
[21]
Simon, R.; Lam, A.; Li, M.; Ngan, M.; Menenzes, S.; Zhao, Y. Analysis of gene expression data using BRB-ArrayTools. Canc. Info, 2007, 3, 11-17.
[22]
Lopez-Romero, P.; Gonzalez, M.A.; Callejas, S.; Dopazo, A.; Irizarry, R.A. Processing of agilent microRNA array data. BMC Res. Notes, 2010, 3, 18.
[23]
Oliveros, J.C. VENNY. An interactive tool for comparing lists with Venn Diagrams http://bioinfogp.cnb.csic.es/tools/venny/index.html
[24]
Vlachos, I.S.; Kostoulas, N.; Vergoulis, T.; Georgakilas, G.; Reczko, M.; Maragkakis, M.; Paraskevopoulou, M.D.; Prionidis, K.; Dalamagas, T.; Hatzigeorgiou, A.G. DIANA miRPath v.2.0: Investigating the Combinatorial Effect of microRNAs in Pathways. Nucleic Acids Res., 2012, 40, 498-504.
[25]
Galanty, A.; Koczurkiewicz, P.; Wnuk, D.; Paw, M.; Karnas, E.; Podolak, I.; Węgrzyn, M.; Borusiewicz, M.; Madeja, Z.; Czyż, J. Usnic acid and atranorin exert selective cytostatic and anti-invasive effects on human prostate and melanoma cancer cells. Toxicol. Vitr., 2017, 40, 161-169.
[26]
Zambare, V.P.; Christopher, L.P. Biopharmaceutical potential of lichens. Pharm. Biol., 2012, 50(6), 778-798.
[27]
Einarsdóttir, E.; Groeneweg, J.; Björnsdóttir, G.G.; Haroardottir, G.; Omarsdóttir, S.; Ingólfsdóttir, K.; Ögmundsdóttir, H.M. Cellular mechanisms of the anticancer effects of the lichen compound usnic acid. Planta Med., 2010, 76(10), 969-974.
[28]
Bačkorová, M.; Bačkor, M.; Mikeš, J.; Jendželovský, R.; Fedoročko, P. Variable responses of different human cancer cells to the lichen compounds parietin, atranorin, usnic acid and gyrophoric acid. Toxicol. Vitr., 2011, 25(1), 37-44.
[29]
Bačkorová, M.; Jendželovský, R.; Kello, M.; Bačkor, M.; Mikeš, J.; Fedoročko, P. Lichen secondary metabolites are responsible for induction of apoptosis in HT-29 and A2780 human cancer cell lines. Toxicol. Vitr., 2012, 26(3), 462-468.
[30]
Song, Z.; Yue, W.; Wei, B.; Wang, N.; Li, T.; Guan, L.; Shi, S.; Zeng, Q.; Pei, X.; Chen, L. Sonic hedgehog pathway is essential for maintenance of cancer stem-like cells in human gastric cancer. PLoS One, 2011, 6(3)e17687
[31]
Jiang, J.; Hui, C. Hedgehog signaling in development and cancer. Dev. Cell, 2008, 15(6), 801-812.
[32]
Hadden, M.K. Hedgehog pathway inhibitors: A patent review (2009--Present). Expert Opin. Ther. Pat., 2013, 23(3), 345-361.
[33]
Li, W.; Sun, Q.; Song, L.; Gao, C.; Liu, F.; Chen, Y.; Jiang, Y. Discovery of 1-(3-Aryl-4-Chlorophenyl)-3-(P-Aryl)urea derivatives against breast cancer by inhibiting PI3K/Akt/mTOR and hedgehog signalings. Eur. J. Med. Chem., 2017, 141, 721-733.
[34]
Kern, D.; Regl, G.; Hofbauer, S.W.; Altenhofer, P.; Achatz, G.; Dlugosz, A.; Schnidar, H.; Greil, R.; Hartmann, T.N.; Aberger, F. Hedgehog/GLI and PI3K Signaling in the Initiation and Maintenance of Chronic Lymphocytic Leukemia. Oncogene, 2015, 34(42), 5341-5351.
[35]
Arnold, K.M.; Pohlig, R.T.; Sims-Mourtada, J. Co-Activation of hedgehog and Wnt signaling pathways is associated with poor outcomes in triple negative breast cancer. Oncol. Lett., 2017, 14(5), 5285-5292.
[36]
Raza, A.; Ghoshal, A.; Chockalingam, S.; Ghosh, S.S. Connexin-43 enhances tumor suppressing activity of artesunate via gap junction-dependent as well as independent pathways in human breast cancer cells. Sci. Rep., 2017, 7(1)
[http://dx.doi.org/10.1038/s41598-017-08058-y]
[37]
Wen, Y.; Han, J.; Chen, J.; Dong, J.; Xia, Y.; Liu, J.; Jiang, Y.; Dai, J.; Lu, J.; Jin, G. Plasma miRNAs as early biomarkers for detecting hepatocellular carcinoma. Int. J. Cancer, 2015, 137(7), 1679-1690.
[38]
Wang, B.; Li, J.; Sun, M.; Sun, L.; Zhang, X. miRNA expression in breast cancer varies with lymph node metastasis and other clinicopathologic features. IUBMB Life, 2014, 66(5), 371-377.
[39]
Petrozza, V.; Carbone, A.; Bellissimo, T.; Porta, N.; Palleschi, G.; Pastore, A.L.; Di Carlo, A.; Della Rocca, C.; Fazi, F. Oncogenic microRNAs characterization in clear cell renal cell carcinoma. Int. J. Mol. Sci., 2015, 16(12), 29219-29225.
[40]
Pei, K.; Zhu, J.J.; Wang, C.E.; Xie, Q.L.; Guo, J.Y. MicroRNA-185-5p modulates chemosensitivity of human non-small cell lung cancer to cisplatin via targeting ABCC1. Eur. Rev. Med. Pharmacol. Sci., 2016, 20(22), 4697-4704.
[41]
Tang, H.; Liu, P.; Yang, L.; Xie, X.; Ye, F.; Wu, M.; Liu, X.; Chen, B.; Zhang, L.; Xie, X. miR-185 suppresses tumor proliferation by directly targeting E2F6 and DNMT1 and indirectly upregulating BRCA1 in triple-negative breast cancer. Mol. Cancer Ther., 2014, 13(12), 3185-3197.
[42]
Li, S.; Ma, Y.; Hou, X.; Liu, Y.; Li, K.; Xu, S.; Wang, J. miR-185 acts as a tumor suppressor by targeting AKT1 in non-small cell lung cancer cells. Int. J. Clin. Exp. Pathol., 2015, 8(9), 11854-11862.


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Article Details

VOLUME: 19
ISSUE: 12
Year: 2019
Page: [1463 - 1472]
Pages: 10
DOI: 10.2174/1871520618666181112120142
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