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Current Pharmaceutical Biotechnology


ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

Research Article

Usnic Acid Inhibits Proliferation and Migration through ATM Mediated DNA Damage Response in RKO Colorectal Cancer Cell

Author(s): Wenbing Wu, Hui Gou, Jingying Dong, Xiaolong Yang, Yanan Zhao, Heng Peng, Dan Chen, Ruiman Geng, Lihong Chen and Ji Liu*

Volume 22, Issue 8, 2021

Published on: 02 October, 2020

Page: [1129 - 1138] Pages: 10

DOI: 10.2174/1389201021666201002155955

Price: $65


Background: Usnic Acid (UA), also known as lichenol, has been reported to have inhibitory effects on a variety of cancer cells, but its specific mechanism remained to be elucidated. Tumor chemotherapy drugs, especially DNA damage chemotherapeutic drugs, target Chromosomal DNA, but their spontaneous and acquired drug resistance are also an urgent problem to be solved. Therefore, drug combination research has become the focus of researchers.

Methods: Here, we evaluated the tumor-suppressing molecular mechanism of UA in colorectal cancer cells RKO from the perspective of the ATM-mediated DNA damage signaling pathway through H2O2 simulating DNA damage chemotherapeutic drugs. CCK8 cell proliferation assay was used to determine the inhibition of RKO cells by hydrogen peroxide and UA alone or in combination, and wound healing assay was applied to determine the effect of the drug on cell migration.

Results: Transfected cells with miRNA18a-5p mimics and inhibitors, MDC and DCFH-DA staining for the measurement of autophagy and ROS, cell cycle and apoptosis were detected by flow cytometry, expressions of microRNA and mRNA were determined by fluorescence quantitative PCR, and protein by Western blot.

Discussion: We found that UA can upregulate ATM via miR-18a to activate the DNA damage signaling pathway and inhibit the proliferation and migration of RKO cells in a concentration-dependent manner.

Conclusion: At the same time, DNA damage responses, including cell cycle, autophagy, apoptosis and ROS levels, are also regulated by UA. Therefore, UA combined with DNA damage chemotherapeutic drugs may be an effective treatment for cancer.

Keywords: Apoptosis, ATM, autophagy, DNA damage, miR-18a, usnic acid.

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Graphical Abstract
Siegel, R.; Desantis, C.; Jemal, A. Colorectal cancer statistics, 2014. CA Cancer J. Clin., 2014, 64(2), 104-117.
[] [PMID: 24639052]
Redondo-Blanco, S.; Fernández, J.; Gutiérrez-Del-Río, I.; Villar, C.J.; Lombó, F. New insights toward colorectal cancer chemotherapy using natural bioactive compounds. Front. Pharmacol., 2017, 8(109), 109.
[] [PMID: 28352231]
Carrassa, L.; Damia, G. DNA damage response inhibitors: Mechanisms and potential applications in cancer therapy. Cancer Treat. Rev., 2017, 60, 139-151.
[] [PMID: 28961555]
Rancoule, C.; Vallard, A.; Guy, J.B.; Espenel, S.; Sauvaigo, S.; Rodriguez-Lafrasse, C.; Magné, N. Impairment of DNA damage response and cancer. Bull. Cancer, 2017, 104(11), 962-970.
[] [PMID: 29132683]
Valko, M.; Izakovic, M.; Mazur, M.; Rhodes, C.J.; Telser, J. Role of oxygen radicals in DNA damage and cancer incidence. Mol. Cell. Biochem., 2004, 266(1-2), 37-56.
[] [PMID: 15646026]
Cadet, J.; Wagner, J.R. Oxidatively generated base damage to cellular DNA by hydroxyl radical and one-electron oxidants: Similarities and differences. Arch. Biochem. Biophys., 2014, 557, 47-54.
[] [PMID: 24820329]
Simizu, S.; Takada, M.; Umezawa, K.; Imoto, M. Requirement of caspase-3(-like) protease-mediated hydrogen peroxide production for apoptosis induced by various anticancer drugs. J. Biol. Chem., 1998, 273(41), 26900-26907.
[] [PMID: 9756937]
Maciąg-Dorszyńska, M.; Węgrzyn, G.; Guzow-Krzemińska, B. Antibacterial activity of lichen secondary metabolite usnic acid is primarily caused by inhibition of RNA and DNA synthesis. FEMS Microbiol. Lett., 2014, 353(1), 57-62.
[] [PMID: 24571086]
Pires, R.H.; Lucarini, R.; Mendes-Giannini, M.J. Effect of usnic acid on Candida orthopsilosis and C. parapsilosis. Antimicrob. Agents Chemother., 2012, 56(1), 595-597.
[] [PMID: 22006006]
Geng, X.; Zhang, X.; Zhou, B.; Zhang, C.; Tu, J.; Chen, X.; Wang, J.; Gao, H.; Qin, G.; Pan, W. Usnic acid induces cycle arrest, apoptosis, and autophagy in gastric cancer cells in vitro and in vivo. Med. Sci. Monit., 2018, 24, 556-566.
[] [PMID: 29374767]
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. In Vitro, 2011, 25(1), 37-44.
[] [PMID: 20837130]
Singh, N.; Nambiar, D.; Kale, R.K.; Singh, R.P. Usnic acid inhibits growth and induces cell cycle arrest and apoptosis in human lung carcinoma A549 cells. Nutr. Cancer, 2013, 65(Suppl. 1), 36-43.
[] [PMID: 23682781]
Yellapu, R.K.; Mittal, V.; Grewal, P.; Fiel, M.; Schiano, T. Acute liver failure caused by ‘fat burners’ and dietary supplements: A case report and literature review. Can. J. Gastroenterol., 2011, 25(3), 157-160.
[] [PMID: 21499580]
Wu, W.; Hou, B.; Tang, C.; Liu, F.; Yang, J.; Pan, T.; Si, K.; Lu, D.; Wang, X.; Wang, J.; Xiong, X.; Liu, J.; Xie, C. (+)-usnic acid inhibits migration of c-KIT positive cells in human colorectal cancer. Evid. Based Complement. Alternat. Med., 2018, 2018, 5149436.
[] [PMID: 30298093]
Yurdacan, B.; Egeli, U.; Guney Eskiler, G.; Eryilmaz, I.E.; Cecener, G.; Tunca, B. Investigation of new treatment option for hepatocellular carcinoma: A combination of sorafenib with usnic acid. J. Pharm. Pharmacol., 2019, 71(7), 1119-1132.
[] [PMID: 31025377]
Machado, N.M.; Ribeiro, A.B.; Nicolella, H.D.; Ozelin, S.D.; Silva, L.H.D.D.; Guissone, A.P.P.; Rinaldi-Neto, F.; Lemos, I.L.L.; Furtado, R.A.; Cunha, W.R.; Rezende, A.A.A.; Spanó, M.A.; Tavares, D.C. Usnic acid attenuates genomic instability in Chinese Hamster Ovary (CHO) cells as well as chemical-induced preneoplastic lesions in rat colon. J. Toxicol. Environ. Health A, 2019, 82(6), 401-410.
[] [PMID: 31066341]
Meschini, S.; Condello, M.; Calcabrini, A.; Marra, M.; Formisano, G.; Lista, P.; De Milito, A.; Federici, E.; Arancia, G. The plant alkaloid voacamine induces apoptosis-independent autophagic cell death on both sensitive and multidrug resistant human osteosarcoma cells. Autophagy, 2008, 4(8), 1020-1033.
[] [PMID: 18838862]
Li, L.; Tan, J.; Miao, Y.; Lei, P.; Zhang, Q. ROS and autophagy: interactions and molecular regulatory mechanisms. Cell. Mol. Neurobiol., 2015, 35(5), 615-621.
[] [PMID: 25722131]
Lord, C.J.; Ashworth, A. The DNA damage response and cancer therapy. Nature, 2012, 481(7381), 287-294.
[] [PMID: 22258607]
Tian, H.; Gao, Z.; Li, H.; Zhang, B.; Wang, G.; Zhang, Q.; Pei, D.; Zheng, J. DNA damage response--a double-edged sword in cancer prevention and cancer therapy. Cancer Lett., 2015, 358(1), 8-16.
[] [PMID: 25528631]
Wu, X.J.; Hua, X. Targeting ROS: selective killing of cancer cells by a cruciferous vegetable derived pro-oxidant compound. Cancer Biol. Ther., 2007, 6(5), 646-647.
[] [PMID: 17387274]
Halliwell, B. Oxidative stress and cancer: have we moved forward? Biochem. J., 2007, 401(1), 1-11.
[] [PMID: 17150040]
Schieber, M.; Chandel, N.S. ROS function in redox signaling and oxidative stress. Curr. Biol., 2014, 24(10), R453-R462.
[] [PMID: 24845678]
Guo, Z.; Kozlov, S.; Lavin, M.F.; Person, M.D.; Paull, T.T. ATM activation by oxidative stress. Science, 2010, 330(6003), 517-521.
[] [PMID: 20966255]
Bakkenist, C.J.; Kastan, M.B. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature, 2003, 421(6922), 499-506.
[] [PMID: 12556884]
Cardarelli, M.; Serino, G.; Campanella, L.; Ercole, P.; De Cicco Nardone, F.; Alesiani, O.; Rossiello, F. Antimitotic effects of usnic acid on different biological systems. Cell. Mol. Life Sci., 1997, 53(8), 667-672.
[] [PMID: 9351470]
Chen, S.; Zhang, Z.; Qing, T.; Ren, Z.; Yu, D.; Couch, L.; Ning, B.; Mei, N.; Shi, L.; Tolleson, W.H.; Guo, L. Activation of the Nrf2 signaling pathway in usnic acid-induced toxicity in HepG2 cells. Arch. Toxicol., 2017, 91(3), 1293-1307.
[] [PMID: 27369375]
Brisdelli, F.; Perilli, M.; Sellitri, D.; Piovano, M.; Garbarino, J.A.; Nicoletti, M.; Bozzi, A.; Amicosante, G.; Celenza, G. Cytotoxic activity and antioxidant capacity of purified lichen metabolites: An in vitro study. Phytother. Res., 2013, 27(3), 431-437.
[] [PMID: 22628260]
Einarsdóttir, E.; Groeneweg, J.; Björnsdóttir, G.G.; Harethardottir, G.; Omarsdóttir, S.; Ingólfsdóttir, K.; Ogmundsdóttir, H.M. Cellular mechanisms of the anticancer effects of the lichen compound usnic acid. Planta Med., 2010, 76(10), 969-974.
[] [PMID: 20143294]
Polewska, J. Autophagy--molecular mechanism, apoptosis and cancer. Postepy Hig. Med. Dosw., 2012, 66, 921-936.
[] [PMID: 23175348]
Chen, S.; Dobrovolsky, V.N.; Liu, F.; Wu, Y.; Zhang, Z.; Mei, N.; Guo, L. The role of autophagy in usnic acid-induced toxicity in hepatic cells. Toxicol. Sci., 2014, 142(1), 33-44.
[] [PMID: 25078063]
Margret, B.; Mar, E.; Eydis, E.; Magnusdottir, I.H.; Ogmundsdottir, M.H.; Sesselja, O.; Ogmundsdottir, H.M. Proton-shuttling lichen compound usnic acid affects mitochondrial and lysosomal function in cancer cells. PLoS One, 2012, 7(12), e51296.
Song, L.; Lin, C.; Wu, Z.; Gong, H.; Zeng, Y.; Wu, J.; Li, M.; Li, J. miR-18a impairs DNA damage response through downregulation of ataxia telangiectasia mutated (ATM) kinase. PLoS One, 2011, 6(9), e25454.
Wu, C.W.; Dong, Y.J.; Liang, Q.Y.; He, X.Q.; Ng, S.S.M.; Chan, F.K.L.; Sung, J.J.Y.; Yu, J. MicroRNA-18a attenuates DNA damage repair through suppressing the expression of ataxia telangiectasia mutated in colorectal cancer. PLoS One, 2013, 8(2), e57036.
Qased, A.B.; Yi, H.; Liang, N.; Ma, S.; Qiao, S.; Liu, X. MicroRNA-18a upregulates autophagy and Ataxia telangiectasia mutated gene expression in HCT116 colon cancer cells. Mol. Med. Rep., 2013, 7(2), 559-564.
[] [PMID: 23229340]
Vasudevan, S.; Tong, Y.; Steitz, J.A. Switching from repression to activation: Micrornas can up-regulate translation. Science, 2007, 318(5858), 1931-1934.
[] [PMID: 18048652]
Liu, M.; Roth, A.; Yu, M.; Morris, R.; Bersani, F.; Rivera, M.N.; Lu, J.; Shioda, T.; Vasudevan, S.; Ramaswamy, S.; Maheswaran, S.; Diederichs, S.; Haber, D.A. The IGF2 intronic miR-483 selectively enhances transcription from IGF2 fetal promoters and enhances tumorigenesis. Genes Dev., 2013, 27(23), 2543-2548.
[] [PMID: 24298054]
Zhang, Y.; Fan, M.; Zhang, X.; Huang, F.; Wu, K.; Zhang, J.; Liu, J.; Huang, Z.; Luo, H.; Tao, L.; Zhang, H. Cellular microRNAs up-regulate transcription via interaction with promoter TATA-box motifs. RNA, 2014, 20(12), 1878-1889.
[] [PMID: 25336585]
Xiao, M.; Li, J.; Li, W.; Wang, Y.; Wu, F.; Xi, Y.; Zhang, L.; Ding, C.; Luo, H.; Li, Y.; Peng, L.; Zhao, L.; Peng, S.; Xiao, Y.; Dong, S.; Cao, J.; Yu, W. MicroRNAs activate gene transcription epigenetically as an enhancer trigger. RNA Biol., 2017, 14(10), 1326-1334.
[] [PMID: 26853707]
Tan, H.; Huang, S.; Zhang, Z.; Qian, X.; Sun, P.; Zhou, X. Pan-cancer analysis on microRNA-associated gene activation. EBioMedicine, 2019, 43, 82-97.
[] [PMID: 30956173]

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