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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

Wogonin Induces Cell Cycle Arrest and Apoptosis of Hepatocellular Carcinoma Cells by Activating Hippo Signaling

Author(s): Keyan Wu, Man Teng, Wei Zhou, Fanglin Lu, Yang Zhou, Jing Zeng, Jie Yang, Xinnong Liu, Yu Zhang, Yanbing Ding* and Weigan Shen*

Volume 22, Issue 8, 2022

Published on: 24 August, 2021

Page: [1551 - 1560] Pages: 10

DOI: 10.2174/1871520621666210824105915

Price: $65

Abstract

Background: Wogonin has been reported to exhibit pharmacological effects against cancer by regulating cell proliferation, metastasis and apoptosis, however, the role of wogonin in hepatocellular carcinoma (HCC) remains poorly elucidated.

Objective: The current study aimed to illustrate whether wogonin influences HCC cell cycle progression and apoptosis by regulating Hippo signaling.

Methods: The effects of wogonin on HCC cell viability, cell cycle progression and apoptosis were analyzed by utilizing CCK-8 and flow cytometry. RNA-seq was employed to analyze the expression profiles between wogonin-treated and control HCC cells, and the selected RNA-seq transcripts were validated by Reverse Transcription-quantitative realtime Polymerase Chain Reaction (RT-qPCR). Immunofluorescence staining was performed to detect the distribution of YAP/TAZ in the nucleus and cytoplasm in HCC cells. Western blotting and human apoptosis array were performed to examine the expression of the indicated genes.

Results: We demonstrated that wogonin induced cell cycle arrest and apoptosis of HCC cell lines SMMC7721 and HCCLM3. RNA-seq analysis showed enrichment in genes associated with cell cycle progression and apoptosis following incubation with wogonin in HCC cells, and the pathways analysis further identified that Hippo signaling pathways highly altered in wogonin-treated cells. Specifically, wogonin increased the phosphorylation of MOB1 and LATS1, promoted translocation of endogenous YAP and TAZ from the nucleus to the cytoplasm, and facilitated phosphorylation of YAP and TAZ. Notably, overexpression of YAP or TAZ partially abrogated the wogonin-mediated HCC cell cycle arrest and apoptosis, and reversed wogonin-mediated suppression of Claspin.

Conclusion: Wogonin induced HCC cell cycle arrest and apoptosis probably by activating MOB1-LATS1 signaling to inhibit the activation of YAP and TAZ, and then decrease the expression of Claspin, suggesting that the understanding of the molecular mechanisms underlying wogonin-induced cell cycle arrest and apoptosis may be useful in HCC therapeutics.

Keywords: Wogonin, apoptosis, Hippo pathway, Claspin, hepatocellular carcinoma, Cell Cycle.

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[1]
Shi, X.; Zhu, H.R.; Liu, T.T.; Shen, X.Z.; Zhu, J.M. The Hippo pathway in hepatocellular carcinoma: Non-coding RNAs in action. Cancer Lett., 2017, 400, 175-182.
[http://dx.doi.org/10.1016/j.canlet.2017.04.032] [PMID: 28461246]
[2]
Huang, Z.; Zhou, J.K.; Wang, K.; Chen, H.; Qin, S.; Liu, J.; Luo, M.; Chen, Y.; Jiang, J.; Zhou, L.; Zhu, L.; He, J.; Li, J.; Pu, W.; Gong, Y.; Li, J.; Ye, Q.; Dong, D.; Hu, H.; Zhou, Z.; Dai, L.; Huang, C.; Wei, X.; Peng, Y. PDLIM1 inhibits tumor metastasis through activating hippo signaling in hepatocellular Carcinoma. Hepatology, 2020, 71(5), 1643-1659.
[http://dx.doi.org/10.1002/hep.30930] [PMID: 31509262]
[3]
Hyun, M.H.; Lee, Y.S.; Kim, J.H.; Lee, C.U.; Jung, Y.K.; Seo, Y.S.; Yim, H.J.; Yeon, J.E.; Byun, K.S. Hepatic resection compared to chemoembolization in intermediate- to advanced-stage hepatocellular carcinoma: A meta-analysis of high-quality studies. Hepatology, 2018, 68(3), 977-993.
[http://dx.doi.org/10.1002/hep.29883] [PMID: 29543988]
[4]
Ahn, J.C.; Teng, P.C.; Chen, P.J.; Posadas, E.; Tseng, H.R.; Lu, S.C.; Yang, J.D. Detection of circulating tumor cells and their implications as a novel biomarker for diagnosis, prognostication, and therapeutic monitoring in hepatocellular carcinoma. Hepatology, 2021, 73(1), 422-436.
[http://dx.doi.org/10.1002/hep.31165]
[5]
Ding, H.; Wang, Y.; Zhang, H. CCND1 silencing suppresses liver cancer stem cell differentiation and overcomes 5-Fluorouracil resistance in hepatocellular carcinoma. J. Pharmacol. Sci., 2020, 143(3), 219-225.
[http://dx.doi.org/10.1016/j.jphs.2020.04.006] [PMID: 32418739]
[6]
Vogel, A.; Saborowski, A. Current strategies for the treatment of intermediate and advanced hepatocellular carcinoma. Cancer Treat. Rev., 2020, 82101946
[http://dx.doi.org/10.1016/j.ctrv.2019.101946] [PMID: 31830641]
[7]
Kudo, M. Systemic therapy for hepatocellular carcinoma: latest advances. Cancers (Basel), 2018, 10(11), 412.
[http://dx.doi.org/10.3390/cancers10110412] [PMID: 30380773]
[8]
Zhu, Y.J.; Zheng, B.; Wang, H.Y.; Chen, L. New knowledge of the mechanisms of sorafenib resistance in liver cancer. Acta Pharmacol. Sin., 2017, 38(5), 614-622.
[http://dx.doi.org/10.1038/aps.2017.5] [PMID: 28344323]
[9]
Ting, C.T.; Li, W.C.; Chen, C.Y.; Tsai, T.H. Preventive and therapeutic role of traditional Chinese herbal medicine in hepatocellular carcinoma. J. Chin. Med. Assoc., 2015, 78(3), 139-144.
[http://dx.doi.org/10.1016/j.jcma.2014.09.003] [PMID: 25447209]
[10]
Hong, M.; Almutairi, M.M.; Li, S.; Li, J. Wogonin inhibits cell cycle progression by activating the glycogen synthase kinase-3 beta in hepatocellular carcinoma. Phytomedicine, 2020, 68153174
[http://dx.doi.org/10.1016/j.phymed.2020.153174]
[11]
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]
[12]
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]
[13]
Huynh, D.L.; Sharma, N.; Kumar Singh, A.; Singh Sodhi, S.; Zhang, J.J.; Mongre, R.K.; Ghosh, M.; Kim, N.; Ho Park, Y.; Kee Jeong, D. Anti-tumor activity of wogonin, an extract from Scutellaria baicalensis, through regulating different signaling pathways. Chin. J. Nat. Med., 2017, 15(1), 15-40.
[http://dx.doi.org/10.1016/S1875-5364(17)30005-5] [PMID: 28259249]
[14]
Hong, M.; Cheng, H.; Song, L.; Wang, W.; Wang, Q.; Xu, D.; Xing, W. Wogonin suppresses the activity of matrix metalloproteinase-9 and inhibits migration and invasion in human hepatocellular carcinoma. Molecules, 2018, 23(2)E384
[http://dx.doi.org/10.3390/molecules23020384] [PMID: 29439451]
[15]
Zheng, Y.; Pan, D. The hippo signaling pathway in development and disease. Dev. Cell, 2019, 50(3), 264-282.
[http://dx.doi.org/10.1016/j.devcel.2019.06.003] [PMID: 31386861]
[16]
Dunn, B.; Ma, X. The dark side of hippo signaling: A cancer promoter role. Fly (Austin), 2017, 11(4), 271-276.
[http://dx.doi.org/10.1080/19336934.2017.1336270] [PMID: 28574763]
[17]
Kim, W.; Khan, S.K.; Liu, Y.; Xu, R.; Park, O.; He, Y.; Cha, B.; Gao, B.; Yang, Y. Hepatic Hippo signaling inhibits protumoural microenvironment to suppress hepatocellular carcinoma. Gut, 2018, 67(9), 1692-1703.
[http://dx.doi.org/10.1136/gutjnl-2017-314061] [PMID: 28866620]
[18]
Liu, X.; Tian, S.; Liu, M.; Jian, L.; Zhao, L. Wogonin inhibits the proliferation and invasion, and induces the apoptosis of HepG2 and Bel7402 HCC cells through NF κB/Bcl-2, EGFR and EGFR downstream ERK/AKT signaling. Int. J. Mol. Med., 2016, 38(4), 1250-1256.
[http://dx.doi.org/10.3892/ijmm.2016.2700] [PMID: 27499272]
[19]
Karimian, A.; Ahmadi, Y.; Yousefi, B. Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage. DNA Repair (Amst.), 2016, 42, 63-71.
[http://dx.doi.org/10.1016/j.dnarep.2016.04.008] [PMID: 27156098]
[20]
Azenha, D.; Lopes, M.C.; Martins, T.C. Claspin functions in cell homeostasis-A link to cancer? DNA Repair (Amst.), 2017, 59, 27-33.
[http://dx.doi.org/10.1016/j.dnarep.2017.09.002] [PMID: 28942358]
[21]
Ma, S.; Meng, Z.; Chen, R.; Guan, K.L. The hippo pathway: biology and pathophysiology. Annu. Rev. Biochem., 2019, 88, 577-604.
[http://dx.doi.org/10.1146/annurev-biochem-013118-111829] [PMID: 30566373]
[22]
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.
[23]
Yu, F.X.; Zhao, B.; Guan, K.L. Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell, 2015, 163(4), 811-828.
[http://dx.doi.org/10.1016/j.cell.2015.10.044] [PMID: 26544935]
[24]
Harvey, K.F.; Zhang, X.; Thomas, D.M. The Hippo pathway and human cancer. Nat. Rev. Cancer, 2013, 13(4), 246-257.
[http://dx.doi.org/10.1038/nrc3458] [PMID: 23467301]
[25]
Johnson, R.; Halder, G. The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment. Nat. Rev. Drug Discov., 2014, 13(1), 63-79.
[http://dx.doi.org/10.1038/nrd4161] [PMID: 24336504]
[26]
Zhang, S.; Zhou, D. Role of the transcriptional coactivators YAP/TAZ in liver cancer. Curr. Opin. Cell Biol., 2019, 61, 64-71.
[http://dx.doi.org/10.1016/j.ceb.2019.07.006] [PMID: 31387016]
[27]
Valero, V., III; Pawlik, T.M.; Anders, R.A. Emerging role of Hpo signaling and YAP in hepatocellular carcinoma. J. Hepatocell. Carcinoma, 2015, 2, 69-78.
[PMID: 27508196]
[28]
Chen, R.; Xie, R.; Meng, Z.; Ma, S.; Guan, K.L. STRIPAK integrates upstream signals to initiate the Hippo kinase cascade. Nat. Cell Biol., 2019, 21(12), 1565-1577.
[http://dx.doi.org/10.1038/s41556-019-0426-y] [PMID: 31792377]
[29]
Smits, V.A.J.; Cabrera, E.; Freire, R.; Gillespie, D.A. Claspin - checkpoint adaptor and DNA replication factor. FEBS J., 2019, 286(3), 441-455.
[http://dx.doi.org/10.1111/febs.14594] [PMID: 29931808]
[30]
Benevolo, M.; Musio, A.; Vocaturo, A.; Donà, M.G.; Rollo, F.; Terrenato, I.; Carosi, M.; Pescarmona, E.; Vocaturo, G.; Mottolese, M. Claspin as a biomarker of human papillomavirus-related high grade lesions of uterine cervix. J. Transl. Med., 2012, 10, 132.
[http://dx.doi.org/10.1186/1479-5876-10-132] [PMID: 22731782]
[31]
Tsimaratou, K.; Kletsas, D.; Kastrinakis, N.G.; Tsantoulis, P.K.; Evangelou, K.; Sideridou, M.; Liontos, M.; Poulias, I.; Venere, M.; Salmas, M.; Kittas, C.; Halazonetis, T.D.; Gorgoulis, V.G. Evaluation of claspin as a proliferation marker in human cancer and normal tissues. J. Pathol., 2007, 211(3), 331-339.
[http://dx.doi.org/10.1002/path.2095] [PMID: 17152083]
[32]
Allera-Moreau, C.; Rouquette, I.; Lepage, B.; Oumouhou, N.; Walschaerts, M.; Leconte, E.; Schilling, V.; Gordien, K.; Brouchet, L.; Delisle, M.B.; Mazieres, J.; Hoffmann, J.S.; Pasero, P.; Cazaux, C. DNA replication stress response involving PLK1, CDC6, POLQ, RAD51 and CLASPIN upregulation prognoses the outcome of early/mid-stage non-small cell lung cancer patients. Oncogenesis, 2012, 1(10)e30
[http://dx.doi.org/10.1038/oncsis.2012.29] [PMID: 23552402]
[33]
Choi, S.H.; Yang, H.; Lee, S.H.; Ki, J.H.; Nam, D.H.; Yoo, H.Y. TopBP1 and Claspin contribute to the radioresistance of lung cancer brain metastases. Mol. Cancer, 2014, 13, 211.
[http://dx.doi.org/10.1186/1476-4598-13-211] [PMID: 25216549]

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