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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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Research Article

Resveratrol Counteracts Hypoxia-Induced Gastric Cancer Invasion and EMT through Hedgehog Pathway Suppression

Author(s): Qin-Hong Xu, Ying Xiao, Xu-Qi Li*, Lin Fan*, Can-Can Zhou, Liang Cheng, Zheng-Dong Jiang and Guang-Hui Wang

Volume 20, Issue 9, 2020

Page: [1105 - 1114] Pages: 10

DOI: 10.2174/1871520620666200402080034

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Abstract

Background: Gastric Cancer (GC) is one of the most malignant and lethal tumors worldwide. The hypoxic microenvironment is correlated with GC cell invasion, metastasis and Epithelial-Mesenchymal Transition (EMT). Resveratrol is a compound extracted from various plants, including grapes, berries, and some traditional Chinese medicines. Recently, the anticancer properties of resveratrol against many cancers have been reported in a range of studies. However, the exact mechanism through which resveratrol prevents GC invasion and metastasis under hypoxic conditions remains unclear.

Objective: The objective of this study is to show to what extent resveratrol could inhibit the hypoxia-induced malignant biological behavior of GC.

Methods: SGC-7901 cells were cultured in a consistent 3% O2 hypoxic condition or 21% O2 normal condition for 48 hours to establish an in vitro hypoxia model. Western blot and qRT-PCR were used to detect EMT markers of SGC- 7901 cells, including E-cadherin, HIF-1a, Vimentin, etc. Transwell Matrigel Invasion Assays were used to test the invasive ability of SGC-7901 cells. The siRNA targeting Gli-1 showed its role in hypoxia-induced EMT and invasion of SGC-7901 cells.

Results: Resveratrol was found to significantly decrease HIF-1α protein levels induced by hypoxia in SGC-7901 cells. HIF-1α accumulation was found to promote cell proliferation, migration, and invasive capacities in addition to EMT changes through the activation of the Hedgehog pathway. These effects were found to be reversed by resveratrol.

Conclusion: Therefore, these data indicate that resveratrol may serve as a potential anticancer agent for the treatment of GC, even in a hypoxic tumor microenvironment.

Keywords: Gastric cancer, hypoxia, epithelial-mesenchymal transition, resveratrol, HIF-1α, hedgehog.

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[1]
Van Cutsem, E.; Sagaert, X.; Topal, B.; Haustermans, K.; Prenen, H. Gastric cancer. Lancet, 2016, 388(10060), 2654-2664.
[http://dx.doi.org/10.1016/S0140-6736(16)30354-3] [PMID: 27156933]
[2]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2019. CA Cancer J. Clin., 2019, 69(1), 7-34.
[http://dx.doi.org/10.3322/caac.21551] [PMID: 30620402]
[3]
Huang, L.; Wu, R.L.; Xu, A.M. Epithelial-mesenchymal transition in gastric cancer. Am. J. Transl. Res., 2015, 7(11), 2141-2158.
[PMID: 26807164]
[4]
Lee, S.Y.; Jeong, E.K.; Ju, M.K.; Jeon, H.M.; Kim, M.Y.; Kim, C.H.; Park, H.G.; Han, S.I.; Kang, H.S. Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer cells by ionizing radiation. Mol. Cancer, 2017, 16(1), 10.
[http://dx.doi.org/10.1186/s12943-016-0577-4] [PMID: 28137309]
[5]
Huang, L.; Xu, A.M.; Liu, S.; Liu, W.; Li, T.J. Cancer-associated fibroblasts in digestive tumors. World J. Gastroenterol., 2014, 20(47), 17804-17818.
[http://dx.doi.org/10.3748/wjg.v20.i47.17804] [PMID: 25548479]
[6]
Kopp, P. Resveratrol, a phytoestrogen found in red wine. A possible explanation for the conundrum of the ‘French paradox’? Eur. J. Endocrinol., 1998, 138(6), 619-620.
[http://dx.doi.org/10.1530/eje.0.1380619] [PMID: 9678525]
[7]
Pirola, L.; Fröjdö, S. Resveratrol: One molecule, many targets. IUBMB Life, 2008, 60(5), 323-332.
[http://dx.doi.org/10.1002/iub.47] [PMID: 18421779]
[8]
Baur, J.A. Resveratrol, sirtuins, and the promise of a DR mimetic. Mech. Ageing Dev., 2010, 131(4), 261-269.
[http://dx.doi.org/10.1016/j.mad.2010.02.007] [PMID: 20219519]
[9]
Wood, L.G.; Wark, P.A.; Garg, M.L. Antioxidant and anti-inflammatory effects of resveratrol in airway disease. Antioxid. Redox Signal., 2010, 13(10), 1535-1548.
[http://dx.doi.org/10.1089/ars.2009.3064] [PMID: 20214495]
[10]
Pavan, A.R.; Silva, G.D.; Jornada, D.H.; Chiba, D.E.; Fernandes, G.F.; Man Chin, C.; Dos Santos, J.L. Unraveling the anticancer effect of curcumin and resveratrol. Nutrients, 2016, 8(11), E628.
[http://dx.doi.org/10.3390/nu8110628] [PMID: 27834913]
[11]
Yu, Y.H.; Chen, H.A.; Chen, P.S.; Cheng, Y.J.; Hsu, W.H.; Chang, Y.W.; Chen, Y.H.; Jan, Y.; Hsiao, M.; Chang, T.Y.; Liu, Y.H.; Jeng, Y.M.; Wu, C.H.; Huang, M.T.; Su, Y.H.; Hung, M.C.; Chien, M.H.; Chen, C.Y.; Kuo, M.L.; Su, J.L. MiR-520h-mediated FOXC2 regulation is critical for inhibition of lung cancer progression by resveratrol. Oncogene, 2013, 32(4), 431-443.
[http://dx.doi.org/10.1038/onc.2012.74] [PMID: 22410781]
[12]
Sinha, D.; Sarkar, N.; Biswas, J.; Bishayee, A. Resveratrol for breast cancer prevention and therapy: Preclinical evidence and molecular mechanisms. Semin. Cancer Biol., 2016, 40-41, 209-232.
[http://dx.doi.org/10.1016/j.semcancer.2015.11.001] [PMID: 26774195]
[13]
Wu, H.; Wang, Y.; Wu, C.; Yang, P.; Li, H.; Li, Z. Resveratrol induces cancer cell apoptosis through MiR-326/PKM2-mediated ER stress and mitochondrial fission. J. Agric. Food Chem., 2016, 64(49), 9356-9367.
[http://dx.doi.org/10.1021/acs.jafc.6b04549] [PMID: 27960279]
[14]
Ferraz da Costa, D.C.; Fialho, E.; Silva, J.L. Cancer chemoprevention by resveratrol: The p53 tumor suppressor protein as a promising molecular target. Molecules, 2017, 22(6), E1014.
[http://dx.doi.org/10.3390/molecules22061014] [PMID: 28629161]
[15]
Yu, B.; Gu, D.; Zhang, X.; Li, J.; Liu, B.; Xie, J. GLI1-mediated regulation of side population is responsible for drug resistance in gastric cancer. Oncotarget, 2017, 8(16), 27412-27427.
[http://dx.doi.org/10.18632/oncotarget.16174] [PMID: 28404967]
[16]
Yang, Q.; Wang, B.; Zang, W.; Wang, X.; Liu, Z.; Li, W.; Jia, J. Resveratrol inhibits the growth of gastric cancer by inducing G1 phase arrest and senescence in a Sirt1-dependent manner. PLoS One, 2013, 8(11), e70627.
[http://dx.doi.org/10.1371/journal.pone.0070627] [PMID: 24278101]
[17]
Yu, H.; Kortylewski, M.; Pardoll, D. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat. Rev. Immunol., 2007, 7(1), 41-51.
[http://dx.doi.org/10.1038/nri1995] [PMID: 17186030]
[18]
Lu, J.; Zhang, L.; Chen, X.; Lu, Q.; Yang, Y.; Liu, J.; Ma, X. SIRT1 counteracted the activation of STAT3 and NF-κB to repress the gastric cancer growth. Int. J. Clin. Exp. Med., 2014, 7(12), 5050-5058.
[PMID: 25664004]
[19]
Aquilano, K.; Baldelli, S.; Rotilio, G.; Ciriolo, M.R. trans-Resveratrol inhibits H2O2-induced adenocarcinoma gastric cells proliferation via inactivation of MEK1/2-ERK1/2-c-Jun signalling axis. Biochem. Pharmacol., 2009, 77(3), 337-347.
[http://dx.doi.org/10.1016/j.bcp.2008.10.034] [PMID: 19038233]
[20]
Gómez-Leduc, T.; Desancé, M.; Hervieu, M.; Legendre, F.; Ollitrault, D.; de Vienne, C.; Herlicoviez, M.; Galéra, P.; Demoor, M. Hypoxia is a critical parameter for chondrogenic differentiation of human umbilical cord blood mesenchymal stem cells in type I/III collagen sponges. Int. J. Mol. Sci., 2017, 18(9), E1933.
[http://dx.doi.org/10.3390/ijms18091933] [PMID: 28885597]
[21]
Knaup, K.X.; Guenther, R.; Stoeckert, J.; Monti, J.M.; Eckardt, K.U.; Wiesener, M.S. HIF is not essential for suppression of experimental tumor growth by mTOR inhibition. J. Cancer, 2017, 8(10), 1809-1817.
[http://dx.doi.org/10.7150/jca.16486] [PMID: 28819378]
[22]
Xie, H.; Simon, M.C. Oxygen availability and metabolic reprogramming in cancer. J. Biol. Chem., 2017, 292(41), 16825-16832.
[http://dx.doi.org/10.1074/jbc.R117.799973] [PMID: 28842498]
[23]
Schito, L.; Semenza, G.L. Hypoxia-inducible factors: Master regulators of cancer progression. Trends Cancer, 2016, 2(12), 758-770.
[http://dx.doi.org/10.1016/j.trecan.2016.10.016] [PMID: 28741521]
[24]
Imai, T.; Horiuchi, A.; Wang, C.; Oka, K.; Ohira, S.; Nikaido, T.; Konishi, I. Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells. Am. J. Pathol., 2003, 163(4), 1437-1447.
[http://dx.doi.org/10.1016/S0002-9440(10)63501-8] [PMID: 14507651]
[25]
Cheng, Z.X.; Sun, B.; Wang, S.J.; Gao, Y.; Zhang, Y.M.; Zhou, H.X.; Jia, G.; Wang, Y.W.; Kong, R.; Pan, S.H.; Xue, D.B.; Jiang, H.C.; Bai, X.W. Nuclear factor-κB-dependent epithelial to mesenchymal transition induced by HIF-1α activation in pancreatic cancer cells under hypoxic conditions. PLoS One, 2011, 6(8), e23752.
[http://dx.doi.org/10.1371/journal.pone.0023752] [PMID: 21887310]
[26]
Trisciuoglio, D.; Gabellini, C.; Desideri, M.; Ragazzoni, Y.; De Luca, T.; Ziparo, E.; Del Bufalo, D. Involvement of BH4 domain of bcl-2 in the regulation of HIF-1-mediated VEGF expression in hypoxic tumor cells. Cell Death Differ., 2011, 18(6), 1024-1035.
[http://dx.doi.org/10.1038/cdd.2010.175] [PMID: 21233846]
[27]
D’Ignazio, L.; Rocha, S. Hypoxia induced NF-κB. Cells, 2016, 5(1), E10.
[http://dx.doi.org/10.3390/cells5010010] [PMID: 27005664]
[28]
Li, W.; Cao, L.; Chen, X.; Lei, J.; Ma, Q. Resveratrol inhibits hypoxia-driven ROS-induced invasive and migratory ability of pancreatic cancer cells via suppression of the Hedgehog signaling pathway. Oncol. Rep., 2016, 35(3), 1718-1726.
[http://dx.doi.org/10.3892/or.2015.4504] [PMID: 26707376]
[29]
Xiao, Z.; Han, Y.; Zhang, Y.; Zhang, X. Hypoxia-regulated human periodontal ligament cells via Wnt/β-catenin signaling pathway. Medicine (Baltimore), 2017, 96(16), e6562.
[http://dx.doi.org/10.1097/MD.0000000000006562] [PMID: 28422843]
[30]
Vergara, D.; Valente, C.M.; Tinelli, A.; Siciliano, C.; Lorusso, V.; Acierno, R.; Giovinazzo, G.; Santino, A.; Storelli, C.; Maffia, M. Resveratrol inhibits the epidermal growth factor-induced epithelial mesenchymal transition in MCF-7 cells. Cancer Lett., 2011, 310(1), 1-8.
[http://dx.doi.org/10.1016/j.canlet.2011.04.009] [PMID: 21794976]
[31]
Bale, A.E.; Yu, K.P. The hedgehog pathway and basal cell carcinomas. Hum. Mol. Genet., 2001, 10(7), 757-762.
[http://dx.doi.org/10.1093/hmg/10.7.757] [PMID: 11257109]
[32]
Harmon, E.B.; Ko, A.H.; Kim, S.K. Hedgehog signaling in gastrointestinal development and disease. Curr. Mol. Med., 2002, 2(1), 67-82.
[http://dx.doi.org/10.2174/1566524023363130] [PMID: 11898849]
[33]
Jeng, K.S.; Sheen, I.S.; Jeng, W.J.; Yu, M.C.; Hsiau, H.I.; Chang, F.Y. High expression of Sonic Hedgehog signaling pathway genes indicates a risk of recurrence of breast carcinoma. OncoTargets Ther., 2013, 7, 79-86.
[http://dx.doi.org/10.2147/OTT.S54702] [PMID: 24403838]
[34]
ten Haaf, A.; Bektas, N.; von Serenyi, S.; Losen, I.; Arweiler, E.C.; Hartmann, A.; Knüchel, R.; Dahl, E. Expression of the glioma-associated oncogene homolog (GLI) 1 in human breast cancer is associated with unfavourable overall survival. BMC Cancer, 2009, 9, 298.
[http://dx.doi.org/10.1186/1471-2407-9-298] [PMID: 19706168]
[35]
Lei, J.; Ma, J.; Ma, Q.; Li, X.; Liu, H.; Xu, Q.; Duan, W.; Sun, Q.; Xu, J.; Wu, Z.; Wu, E. Hedgehog signaling regulates hypoxia induced epithelial to mesenchymal transition and invasion in pancreatic cancer cells via a ligand-independent manner. Mol. Cancer, 2013, 12, 66.
[http://dx.doi.org/10.1186/1476-4598-12-66] [PMID: 23786654]
[36]
Livak, K.J.; Schmittgen, T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)). Method. Methods, 2001, 25(4), 402-408.
[http://dx.doi.org/10.1006/meth.2001.1262] [PMID: 11846609]
[37]
Cao, L.; Chen, X.; Xiao, X.; Ma, Q.; Li, W. Resveratrol inhibits hyperglycemia-driven ROS-induced invasion and migration of pancreatic cancer cells via suppression of the ERK and p38 MAPK signaling pathways. Int. J. Oncol., 2016, 49(2), 735-743.
[http://dx.doi.org/10.3892/ijo.2016.3559] [PMID: 27278736]
[38]
Gao, Q.; Yuan, Y.; Gan, H.Z.; Peng, Q. Resveratrol inhibits the hedgehog signaling pathway and epithelial-mesenchymal transition and suppresses gastric cancer invasion and metastasis. Oncol. Lett., 2015, 9(5), 2381-2387.
[http://dx.doi.org/10.3892/ol.2015.2988] [PMID: 26137075]
[39]
Lei, J.; Fan, L.; Wei, G.; Chen, X.; Duan, W.; Xu, Q.; Sheng, W.; Wang, K.; Li, X. Gli-1 is crucial for hypoxia-induced epithelial-mesenchymal transition and invasion of breast cancer. Tumour Biol., 2015, 36(4), 3119-3126.
[http://dx.doi.org/10.1007/s13277-014-2948-z] [PMID: 25501705]
[40]
Luoto, K.R.; Kumareswaran, R.; Bristow, R.G. Tumor hypoxia as a driving force in genetic instability. Genome Integr., 2013, 4(1), 5.
[http://dx.doi.org/10.1186/2041-9414-4-5] [PMID: 24152759]
[41]
Ye, L.Y.; Zhang, Q.; Bai, X.L.; Pankaj, P.; Hu, Q.D.; Liang, T.B. Hypoxia-inducible factor 1α expression and its clinical significance in pancreatic cancer: A meta-analysis. Pancreatology, 2014, 14(5), 391-397.
[http://dx.doi.org/10.1016/j.pan.2014.06.008] [PMID: 25278309]
[42]
Nieto, M.A.; Huang, R.Y.; Jackson, R.A.; Thiery, J.P. EMT: 2016. Cell, 2016, 166(1), 21-45.
[http://dx.doi.org/10.1016/j.cell.2016.06.028] [PMID: 27368099]
[43]
Abdel-Rahman, O. Hedgehog pathway aberrations and gastric cancer; evaluation of prognostic impact and exploration of therapeutic potentials. Tumour Biol., 2015, 36(3), 1367-1374.
[http://dx.doi.org/10.1007/s13277-015-3216-6] [PMID: 25680409]
[44]
Gu, H.; Li, X.U.; Zhou, C.; Wen, Y.; Shen, Y.; Zhou, L.; Li, J. Effects and mechanisms of blocking the hedgehog signaling pathway in human gastric cancer cells. Oncol. Lett., 2015, 9(5), 1997-2002.
[http://dx.doi.org/10.3892/ol.2015.3032] [PMID: 26137001]
[45]
Chen, J.; Imanaka, N.; Chen, J.; Griffin, J.D. Hypoxia potentiates Notch signaling in breast cancer leading to decreased E-cadherin expression and increased cell migration and invasion. Br. J. Cancer, 2010, 102(2), 351-360.
[http://dx.doi.org/10.1038/sj.bjc.6605486] [PMID: 20010940]
[46]
Bijlsma, M.F.; Groot, A.P.; Oduro, J.P.; Franken, R.J.; Schoenmakers, S.H.; Peppelenbosch, M.P.; Spek, C.A. Hypoxia induces a hedgehog response mediated by HIF-1alpha. J. Cell. Mol. Med., 2009, 13(8B), 2053-2060.
[http://dx.doi.org/10.1111/j.1582-4934.2008.00491.x] [PMID: 18774959]
[47]
Wang, G.; Zhang, Z.; Xu, Z.; Yin, H.; Bai, L.; Ma, Z.; Decoster, M.A.; Qian, G.; Wu, G. Activation of the sonic hedgehog signaling controls human pulmonary arterial smooth muscle cell proliferation in response to hypoxia. Biochim. Biophys. Acta, 2010, 1803(12), 1359-1367.
[http://dx.doi.org/10.1016/j.bbamcr.2010.09.002] [PMID: 20840857]
[48]
Sims-Mourtada, J.; Yang, D.; Tworowska, I.; Larson, R.; Smith, D.; Tsao, N.; Opdenaker, L.; Mourtada, F.; Woodward, W. Detection of canonical hedgehog signaling in breast cancer by 131-iodine-labeled derivatives of the sonic hedgehog protein. J. Biomed. Biotechnol., 2012, 2012, 639562.
[http://dx.doi.org/10.1155/2012/639562] [PMID: 22811598]
[49]
Li, X.; Wang, D.; Zhao, Q.C.; Shi, T.; Chen, J. Resveratrol inhibited non-small cell lung cancer through inhibiting STAT-3 signaling. Am. J. Med. Sci., 2016, 352(5), 524-530.
[http://dx.doi.org/10.1016/j.amjms.2016.08.027] [PMID: 27865301]
[50]
Bai, Y.; Yang, H.; Zhang, G.; Hu, L.; Lei, Y.; Qin, Y.; Yang, Y.; Wang, Q.; Li, R.; Mao, Q. Inhibitory effects of resveratrol on the adhesion, migration and invasion of human bladder cancer cells. Mol. Med. Rep., 2017, 15(2), 885-889.
[http://dx.doi.org/10.3892/mmr.2016.6051] [PMID: 28000872]
[51]
Karimi Dermani, F.; Saidijam, M.; Amini, R.; Mahdavinezhad, A.; Heydari, K.; Najafi, R. Resveratrol inhibits proliferation, invasion, and epithelial-mesenchymal transition by increasing miR-200c expression in HCT-116 colorectal cancer cells. J. Cell. Biochem., 2017, 118(6), 1547-1555.
[http://dx.doi.org/10.1002/jcb.25816] [PMID: 27918105]
[52]
Azios, N.G.; Dharmawardhane, S.F. Resveratrol and estradiol exert disparate effects on cell migration, cell surface actin structures, and focal adhesion assembly in MDA-MB-231 human breast cancer cells. Neoplasia, 2005, 7(2), 128-140.
[http://dx.doi.org/10.1593/neo.04346] [PMID: 15802018]
[53]
Kozuki, Y.; Miura, Y.; Yagasaki, K. Resveratrol suppresses hepatoma cell invasion independently of its anti-proliferative action. Cancer Lett., 2001, 167(2), 151-156.
[http://dx.doi.org/10.1016/S0304-3835(01)00476-1] [PMID: 11369135]

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