Login Register Cart 0
Generic placeholder image

Protein & Peptide Letters

Editor-in-Chief

ISSN (Print): 0929-8665
ISSN (Online): 1875-5305

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Wogonin Restrains the Malignant Progression of Lung Cancer Through Modulating MMP1 and PI3K/AKT Signaling Pathway

Author(s): Junhao Guo, Gang Jin, Yanjing Hu, Zhi Zhao*, Fangyuan Nan, Xin Hu, Yunsheng Hu and Qun Han

Volume 30, Issue 1, 2023

Published on: 21 November, 2022

Page: [25 - 34] Pages: 10

DOI: 10.2174/0929866530666221027152204

Price: $65

conference banner
Abstract

Background: Wogonin, a natural flavonoid compound, represses cancer cell growth and induces cancer cell apoptosis in diverse malignancies. However, the function of Wogonin in lung cancer cells and its regulatory mechanism deserve to be identified.

Methods: A549 and H460 cells were treated with Wogonin, and the cell growth, apoptosis, migration and invasion were measured by CCK-8 and EdU, flow cytometry and Transwell assays. The targeted genes of Wogonin and lung cancer were identified from the TCMSP and Genecards databases, respectively. The STRING database and Cytoscape software were used to establish a PPI network and screen hub genes. GO and KEGG analysis was conducted to explore the functions and signal pathways related to the hub genes. MMP1 expression in lung cancer was analyzed using the UALCAN databases, and GSEA was performed utilizing LinkedOmics. Gelatin zymography assay was used to detect MMP1 activity. MMP1 mRNA expression was detected by qRT-PCR. Besides, MMP1, p-AKT and c-Myc protein were detected by Western Blot assay.

Results: Wogonin could suppress the proliferation, migration and invasion of A549 and H460 cells and induce apoptosis. GO and KEGG enrichment analysis revealed the hub genes were mostly enriched in re-entry into the mitotic cell cycle and apoptosis. The expression of MMP1 was markedly upregulated in lung squamous cell carcinoma, lung adenocarcinoma tissues, and lung cancer cell lines. Wogonin could significantly inhibit MMP1 expression and activity, and overexpression of MMP1 significantly reversed the effect of Wogonin on the malignant phenotypes of A549 and H460 cells. Wogonin inhibited the expression of p-AKT and c-Myc protein by regulating MMP1.

Conclusion: Wogonin can repress lung cancer cells' growth and metastatic potential and promote cell apoptosis via repressing MMP1 expression and modulating PI3K/AKT signaling pathway.

« Previous Next »
Graphical Abstract

[1]
Torre, L.A.; Bray, F.; Siegel, R.L.; Ferlay, J.; Lortet-Tieulent, J.; Jemal, A. Global cancer statistics, 2012. CA Cancer J. Clin., 2015, 65(2), 87-108.
[http://dx.doi.org/10.3322/caac.21262] [PMID: 25651787]
[2]
Cheng, B.; Xiong, S.; Li, C.; Liang, H.; Zhao, Y.; Li, J.; Shi, J.; Ou, L.; Chen, Z.; Liang, P.; Liang, W.; He, J. An annual review of the remarkable advances in lung cancer clinical research in 2019. J. Thorac. Dis., 2020, 12(3), 1056-1069.
[http://dx.doi.org/10.21037/jtd.2020.03.11] [PMID: 32274174]
[3]
Zhang, C.; Wu, W.; Yang, J.; Sun, J. Application of artificial intelligence in respiratory medicine. J. Digital Health, 2022, 1, 30-39.
[http://dx.doi.org/10.55976/jdh.1202215330-39]
[4]
Guan, F.; Ding, Y.; Zhang, Y.; Zhou, Y.; Li, M.; Wang, C. Curcumin suppresses proliferation and migration of MDA-MB-231 breast cancer cells through autophagy-dependent Akt degradation. PLoS One, 2016, 11(1), e014655.
[http://dx.doi.org/10.1371/journal.pone.0146553] [PMID: 26752181]
[5]
Wang, Y.; Liu, Q.; Liu, Z.; Li, B.; Sun, Z.; Zhou, H.; Zhang, X.; Gong, Y.; Shao, C. Berberine, a genotoxic alkaloid, induces ATM-Chk1 mediated G2 arrest in prostate cancer cells. Mutat. Res., 2012, 734(1-2), 20-29.
[http://dx.doi.org/10.1016/j.mrfmmm.2012.04.005] [PMID: 22561209]
[6]
Wang, J.H.; Nao, J.F.; Zhang, M.; He, P. 20(s)-ginsenoside Rg3 promotes apoptosis in human ovarian cancer HO-8910 cells through PI3K/Akt and XIAP pathways. Tumour Biol., 2014, 35(12), 11985-11994.
[http://dx.doi.org/10.1007/s13277-014-2497-5] [PMID: 25168366]
[7]
Rawat, S.; Gupta, G.; Pathak, S.; Singh, S.K.; Singh, H.; Mishra, A.; Gilhotra, R.; Aljabali, A.A.A.; Dureja, H.; Tambuwala, M.M.; Chellappan, D.K.; Dua, K. Current biological and pharmacological updates on wogonin. EXCLI J., 2020, 19, 635-640.
[PMID: 32536834]
[8]
Zhao, Q.; Chang, W.; Chen, R.; Liu, Y. Anti-proliferative effect of wogonin on ovary cancer cells involves activation of apoptosis and cell cycle arrest. Med. Sci. Monit., 2019, 25, 8465-8471.
[http://dx.doi.org/10.12659/MSM.917823] [PMID: 31707402]
[9]
Wang, Y.; Chen, S.; Sun, S.; Liu, G.; Chen, L.; Xia, Y.; Cui, J.; Wang, W.; Jiang, X.; Zhang, L.; Zhu, Y.; Zou, Y.; Shi, B. Wogonin induces apoptosis and reverses sunitinib resistance of renal cell carcinoma cells via inhibiting CDK4-RB pathway. Front. Pharmacol., 2020, 11, 1152.
[http://dx.doi.org/10.3389/fphar.2020.01152] [PMID: 32792963]
[10]
He, L.; Lu, N.; Dai, Q.; Zhao, Y.; Zhao, L.; Wang, H.; Li, Z.; You, Q.; Guo, Q. Wogonin induced G1 cell cycle arrest by regulating Wnt/β-catenin signaling pathway and inactivating CDK8 in human colorectal cancer carcinoma cells. Toxicology, 2013, 312, 36-47.
[http://dx.doi.org/10.1016/j.tox.2013.07.013] [PMID: 23907061]
[11]
Wang, C.; Cui, C. Inhibition of lung cancer proliferation by wogonin is associated with the activation of apoptosis and generation of reactive oxygen species. Balkan Med. J., 2019, 37(1), 29-33.
[http://dx.doi.org/10.4274/balkanmedj.galenos.2019.2019.7.75] [PMID: 31594288]
[12]
Huang, H. Matrix metalloproteinase-9 (MMP-9) as a cancer biomarker and MMP-9 biosensors: Recent advances. Sensors, 2018, 18(10), 3249.
[http://dx.doi.org/10.3390/s18103249] [PMID: 30262739]
[13]
Jiang, S.; Liu, H.; Zhang, J.; Zhang, F.; Fan, J.; Liu, Y. MMP1 regulated by NEAT1/miR-361-5p axis facilitates the proliferation and migration of cutaneous squamous cell carcinoma via the activation of Wnt pathway. Cancer Biol. Ther., 2021, 22(5-6), 381-391.
[http://dx.doi.org/10.1080/15384047.2021.1941583] [PMID: 34369270]
[14]
Liu, H.; Lan, T.; Li, H.; Xu, L.; Chen, X.; Liao, H.; Chen, X.; Du, J.; Cai, Y.; Wang, J.; Li, X.; Huang, J.; Yuan, K.; Zeng, Y. Circular RNA circDLC1 inhibits MMP1-mediated liver cancer progression via interaction with HuR. Theranostics, 2021, 11(3), 1396-1411.
[http://dx.doi.org/10.7150/thno.53227] [PMID: 33391541]
[15]
Wang, K.; Zheng, J.; Yu, J.; Wu, Y.; Guo, J.; Xu, Z.; Sun, X. Knockdown of MMP 1 inhibits the progression of colorectal cancer by suppressing the PI3K/Akt/c myc signaling pathway and EMT. Oncol. Rep., 2020, 43(4), 1103-1112.
[http://dx.doi.org/10.3892/or.2020.7490] [PMID: 32323782]
[16]
Gabasa, M.; Radisky, E.S.; Ikemori, R.; Bertolini, G.; Arshakyan, M.; Hockla, A.; Duch, P.; Rondinone, O.; Llorente, A.; Maqueda, M.; Davalos, A.; Gavilán, E.; Perera, A.; Ramírez, J.; Gascón, P.; Reguart, N.; Roz, L.; Radisky, D.C.; Alcaraz, J. MMP1 drives tumor progression in large cell carcinoma of the lung through fibroblast senescence. Cancer Lett., 2021, 507, 1-12.
[http://dx.doi.org/10.1016/j.canlet.2021.01.028] [PMID: 33684534]
[17]
Li, Y.; Huang, H.; Ye, X.; Huang, Z.; Chen, X.; Wu, F.; Lin, T. miR-202-3p negatively regulates MMP-1 to inhibit the proliferation, migration and invasion of lung adenocarcinoma cells. Cell Cycle, 2021, 20(4), 406-416.
[http://dx.doi.org/10.1080/15384101.2021.1876390] [PMID: 33487115]
[18]
Huang, K.F.; Zhuang, Y.; Huang, Y.Q.; Diao, Y. Experimental study on inhibitory effect of wogonin on proliferation and invasion of breast cancer cells. Zhongguo Zhongyao Zazhi, 2014, 39(8), 1485-1489.
[PMID: 25039187]
[19]
Wang, S.J.; Zhao, J.K.; Ren, S.; Sun, W.W.; Zhang, W.J.; Zhang, J.N. Wogonin affects proliferation and the energy metabolism of SGC-7901 and A549 cells. Exp. Ther. Med., 2019, 17(1), 911-918.
[PMID: 30651880]
[20]
Chen, X.; Bai, Y.; Zhong, Y.; Xie, X.; Long, H.; Yang, Y.; Wu, S.; Jia, Q.; Wang, X. Wogonin has multiple anti-cancer effects by regulating c-Myc/SKP2/Fbw7α and HDAC1/HDAC2 pathways and inducing apoptosis in human lung adenocarcinoma cell line A549. PLoS One, 2013, 8(11), e79201.
[http://dx.doi.org/10.1371/journal.pone.0079201] [PMID: 24265759]
[21]
He, F.; Wang, Q.; Zheng, X.L.; Yan, J.Q.; Yang, L.; Sun, H.; Hu, L.N.; Lin, Y.; Wang, X. Wogonin potentiates cisplatin-induced cancer cell apoptosis through accumulation of intracellular reactive oxygen species. Oncol. Rep., 2012, 28(2), 601-605.
[http://dx.doi.org/10.3892/or.2012.1841] [PMID: 22665077]
[22]
Zhao, Y.; Yao, J.; Wu, X.P.; Zhao, L.; Zhou, Y.X.; Zhang, Y.; You, Q.D.; Guo, Q.L.; Lu, N. Wogonin suppresses human alveolar adenocarcinoma cell A549 migration in inflammatory microenvironment by modulating the IL-6/STAT3 signaling pathway. Mol. Carcinog., 2015, 54(S1), E81-E93.
[http://dx.doi.org/10.1002/mc.22182] [PMID: 24976450]
[23]
Chambers, A.F.; Matrisian, L.M. Changing views of the role of matrix metalloproteinases in metastasis. J. Natl. Cancer Inst., 1997, 89(17), 1260-1270.
[http://dx.doi.org/10.1093/jnci/89.17.1260] [PMID: 9293916]
[24]
Kessenbrock, K.; Plaks, V.; Werb, Z. Matrix metalloproteinases: Regulators of the tumor microenvironment. Cell, 2010, 141(1), 52-67.
[http://dx.doi.org/10.1016/j.cell.2010.03.015] [PMID: 20371345]
[25]
Sauter, W.; Rosenberger, A.; Beckmann, L.; Kropp, S.; Mittelstrass, K.; Timofeeva, M.; Wölke, G.; Steinwachs, A.; Scheiner, D.; Meese, E.; Sybrecht, G.; Kronenberg, F.; Dienemann, H.; Chang-Claude, J.; Illig, T.; Wichmann, H.E.; Bickeböller, H.; Risch, A. Matrix metalloproteinase 1 (MMP1) is associated with early-onset lung cancer. Cancer Epidemiol. Biomarkers Prev., 2008, 17(5), 1127-1135.
[http://dx.doi.org/10.1158/1055-9965.EPI-07-2840] [PMID: 18483334]
[26]
Fang, W.; Zhou, X.; Wang, J.; Xu, L.; Zhou, L.; Yu, W.; Tao, Y.; Zhu, J.; Hu, B.; Liang, C.; Li, F.; Hua, J.; Chen, Q. Wogonin mitigates intervertebral disc degeneration through the Nrf2/ARE and MAPK signaling pathways. Int. Immunopharmacol., 2018, 65, 539-549.
[http://dx.doi.org/10.1016/j.intimp.2018.10.024] [PMID: 30412851]
[27]
Park, J.S.; Lee, H.J.; Lee, D.Y.; Jo, H.S.; Jeong, J.H.; Kim, D.H.; Nam, D.C.; Lee, C.J.; Hwang, S.C. Chondroprotective effects of wogonin in experimental models of osteoarthritis in vitro and in vivo. Biomol. Ther., 2015, 23(5), 442-448.
[http://dx.doi.org/10.4062/biomolther.2015.045] [PMID: 26336584]
[28]
Vara, J.Á.F.; Casado, E.; de Castro, J.; Cejas, P.; Belda-Iniesta, C.; González-Barón, M. PI3K/Akt signalling pathway and cancer. Cancer Treat. Rev., 2004, 30(2), 193-204.
[http://dx.doi.org/10.1016/j.ctrv.2003.07.007] [PMID: 15023437]
[29]
Zhang, X.; He, X.; Liu, Y.; Zhang, H.; Chen, H.; Guo, S.; Liang, Y. MiR-101-3p inhibits the growth and metastasis of non-small cell lung cancer through blocking PI3K/AKT signal pathway by targeting MALAT-1. Biomed. Pharmacother., 2017, 93, 1065-1073.
[http://dx.doi.org/10.1016/j.biopha.2017.07.005] [PMID: 28738500]
[30]
Tan, H.; Li, X.; Yang, W.H.; Kang, Y. A flavone, Wogonin from Scutellaria baicalensis inhibits the proliferation of human colorectal cancer cells by inducing of autophagy, apoptosis and G2/M cell cycle arrest via modulating the PI3K/AKT and STAT3 signalling pathways. J. Buon, 2019, 24(3), 1143-1149.
[PMID: 31424673]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy