Baicalin target protein, Annexin A2, is a target of new antitumor drugs.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
18 Sep 2024
18 Sep 2024
Historique:
received:
03
07
2023
accepted:
24
07
2024
medline:
19
9
2024
pubmed:
19
9
2024
entrez:
18
9
2024
Statut:
epublish
Résumé
Baicalin is a flavonoid extracted from Scutellaria baicalensis Georgi. As it has significant antitumor and apoptosis-inducing effects, baicalin may be useful as a lead compound in new antitumor drug development. However, as the pharmacological actions of baicalin have yet to be elucidated, we isolated its target protein, which was successfully identified as Annexin A2. Annexin A2 forms a heterotetramer with S100A10 protein, which plays an important role in the plasminogen activator system. The heterotetramer bound to tissue plasminogen activator (tPA) activates the conversion of plasminogen to plasmin and promotes the expression of STAT-3 and NF-κB, which are target genes involved in the development of cancer. Moreover, NF-κB and STAT-3 induce the expression of cell inhibitors of apoptotic proteins and inhibit apoptosis. To examine whether these antitumor and apoptosis-inducing effects of baicalin are mediated by Annexin A2, we prepared Annexin A2 knockdown HepG2 cells. We compared mRNA expression by RT-qPCR and apoptosis by caspase-3 activity assays in Annexin A2 knockdown HepG2 cells. The results showed that the antitumor and apoptosis-inducing effects of baicalin are mediated by Annexin A2. The results of this study suggest that agents capable of inhibiting Annexin A2 may be useful candidates for the development of novel antitumor agents.
Identifiants
pubmed: 39294172
doi: 10.1038/s41598-024-68528-y
pii: 10.1038/s41598-024-68528-y
doi:
Substances chimiques
baicalin
347Q89U4M5
Annexin A2
0
Flavonoids
0
Antineoplastic Agents
0
ANXA2 protein, human
0
STAT3 Transcription Factor
0
NF-kappa B
0
S100 calcium binding protein A10
0
S100 Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
21814Subventions
Organisme : Japan Society for the Promotion of Science
ID : 21K08358
Organisme : Japan Society for the Promotion of Science
ID : 22K08392
Informations de copyright
© 2024. The Author(s).
Références
Gao, Z., Huang, K. & Xu, H. Protective effects of flavonoids in the roots of Scutellaria baicalensis Georgi against hydrogen peroxide-induced oxidative stress in HS-SY5Y cells. Pharmacol. Res. 43(2), 173–178 (2001).
pubmed: 11243719
doi: 10.1006/phrs.2000.0761
Shen, Y. C. et al. Mechanisms in mediating the anti-inflammatory effects of baicalin and baicalein in human leukocytes. Eur. J. Pharmacol. 465(1–2), 171–181 (2003).
pubmed: 12650847
doi: 10.1016/S0014-2999(03)01378-5
Dong, L. H. et al. Baicalin inhibits PDGF-BB-stimulated vascular smooth muscle cell proliferation through suppressing PDGFRβ-ERK signaling and increase in p27 accumulation and prevents injury-induced neointimal hyperplasia. Cell Res. 20(11), 1252–1262 (2010).
pubmed: 20661261
doi: 10.1038/cr.2010.111
Yu, Y., Pei, M. & Li, L. Baicalin induces apoptosis in hepatic cancer cells in vitro and suppresses tumor growth in vivo. Int. J. Clin. Exp. Med. 8(6), 8958–8967 (2015).
pubmed: 26309548
pmcid: 4538000
Chen, W. C. et al. Baicalin induces apoptosis in SW620 human colorectal carcinoma cells in vitro and suppresses tumor growth in vivo. Molecules 17(4), 3844–3857 (2012).
pubmed: 22456615
pmcid: 6268256
doi: 10.3390/molecules17043844
Lin, C. et al. AKT serine/threonine protein kinase modulates baicalin-triggered autophagy in human bladder cancer T24 cells. Int. J. Oncol. 42(3), 993–1000 (2013).
pubmed: 23354080
doi: 10.3892/ijo.2013.1791
Kong, N. et al. Baicalin induces ferroptosis in bladder cancer cells by downregulating FTH1. Acta Pharm. Sin. B 11(12), 4045–4054 (2021).
pubmed: 35024325
pmcid: 8727776
doi: 10.1016/j.apsb.2021.03.036
Zhu, Y. et al. Baicalin suppresses proliferation, migration, and invasion in human glioblastoma cells via Ca(2+)-dependent pathway. Drug Des. Dev. Ther. 12, 3247–3261 (2018).
doi: 10.2147/DDDT.S176403
Shehatta, N. H. et al. Baicalin; a promising chemopreventive agent, enhances the antitumor effect of 5-FU against breast cancer and inhibits tumor growth and angiogenesis in Ehrlich solid tumor. Biomed. Pharmacother. 146, 112599 (2022).
pubmed: 34968922
doi: 10.1016/j.biopha.2021.112599
Zhou, Q. M. et al. The combination of baicalin and baicalein enhances apoptosis via the ERK/p38 MAPK pathway in human breast cancer cells. Acta Pharmacol. Sin. 30(12), 1648–1658 (2009).
pubmed: 19960010
pmcid: 4007493
doi: 10.1038/aps.2009.166
Gerke, V. & Weber, K. Identity of p36K phosphorylated upon Rous sarcoma virus transformation with a protein purified from brush borders; calcium-dependent binding to non-erythroid spectrin and F-actin. Embo J. 3(1), 227–233 (1984).
pubmed: 6323166
pmcid: 557325
doi: 10.1002/j.1460-2075.1984.tb01789.x
Huang, Y. et al. Down-regulation of the PI3K/Akt signaling pathway and induction of apoptosis in CA46 Burkitt lymphoma cells by baicalin. J. Exp. Clin. Cancer Res. 31(1), 48 (2012).
pubmed: 22607709
pmcid: 3403945
doi: 10.1186/1756-9966-31-48
Al-Qahtani, S. M. et al. The association between Annexin A2 and epithelial cell adhesion molecule in breast cancer cells. Cancer Rep. 5, e1498 (2022).
doi: 10.1002/cnr2.1498
Gao, S. et al. The calcimedin Annexin A3 displays tumor-promoting effect in esophageal squamous cell carcinoma by activating NF-κB signaling. Mamm. Genome 32(5), 381–388 (2021).
pubmed: 34109455
doi: 10.1007/s00335-021-09883-3
Guo, C. et al. 33-kDa ANXA3 isoform contributes to hepatocarcinogenesis via modulating ERK, PI3K/Akt-HIF and intrinsic apoptosis pathways. J. Adv. Res. 30, 85–102 (2021).
pubmed: 34026289
doi: 10.1016/j.jare.2020.11.003
Cañas, F. et al. Annexin A2 autoantibodies in thrombosis and autoimmune diseases. Thromb. Res. 135(2), 226–230 (2015).
pubmed: 25533130
doi: 10.1016/j.thromres.2014.11.034
Lokman, N. A. et al. Annexin A2 is regulated by ovarian cancer-peritoneal cell interactions and promotes metastasis. Oncotarget 4(8), 1199–1211 (2013).
pubmed: 23945256
pmcid: 3787151
doi: 10.18632/oncotarget.1122
Díaz, V. M. et al. Specific interaction of tissue-type plasminogen activator (t-PA) with annexin II on the membrane of pancreatic cancer cells activates plasminogen and promotes invasion in vitro. Gut 53(7), 993–1000 (2004).
pubmed: 15194650
pmcid: 1774091
doi: 10.1136/gut.2003.026831
Sharma, M., Ownbey, R. T. & Sharma, M. C. Breast cancer cell surface annexin II induces cell migration and neoangiogenesis via tPA dependent plasmin generation. Exp. Mol. Pathol. 88(2), 278–286 (2010).
pubmed: 20079732
doi: 10.1016/j.yexmp.2010.01.001
Li, Q. et al. Plasmin triggers cytokine induction in human monocyte-derived macrophages. Arterioscler. Thromb. Vasc. Biol. 27(6), 1383–1389 (2007).
pubmed: 17413040
doi: 10.1161/ATVBAHA.107.142901
Godier, A. & Hunt, B. J. Plasminogen receptors and their role in the pathogenesis of inflammatory, autoimmune and malignant disease. J. Thromb. Haemost. 11(1), 26–34 (2013).
pubmed: 23140188
doi: 10.1111/jth.12064
Wang, L., Du, H. & Chen, P. Chlorogenic acid inhibits the proliferation of human lung cancer A549 cell lines by targeting Annexin A2 in vitro and in vivo. Biomed. Pharmacother. 131, 110673 (2020).
pubmed: 32882585
doi: 10.1016/j.biopha.2020.110673
Chen, L. et al. Annexin A2 regulates glioma cell proliferation through the STAT3-cyclin D1 pathway. Oncol. Rep. 42(1), 399–413 (2019).
pubmed: 31115554
Fan, Y., Mao, R. & Yang, J. NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer. Protein Cell 4(3), 176–185 (2013).
pubmed: 23483479
pmcid: 4875500
doi: 10.1007/s13238-013-2084-3
He, G. & Karin, M. NF-κB and STAT3—Key players in liver inflammation and cancer. Cell Res. 21(1), 159–168 (2011).
pubmed: 21187858
doi: 10.1038/cr.2010.183
Yin, D. et al. LINC01133 promotes hepatocellular carcinoma progression by sponging miR-199a-5p and activating annexin A2. Clin. Transl. Med. 11(5), e409 (2021).
pubmed: 34047479
pmcid: 8101537
doi: 10.1002/ctm2.409
Zheng, L. & Jaffee, E. M. Annexin A2 is a new antigenic target for pancreatic cancer immunotherapy. Oncoimmunology 1(1), 112–114 (2012).
pubmed: 22720228
pmcid: 3376961
doi: 10.4161/onci.1.1.18017
Kumble, K. D. et al. Enhanced levels of annexins in pancreatic carcinoma cells of Syrian hamsters and their intrapancreatic allografts. Cancer Res. 52(1), 163–167 (1992).
pubmed: 1530768
Ağababaoğlu, İ et al. Chaperonin (HSP60) and annexin-2 are candidate biomarkers for non-small cell lung carcinoma. Medicine 96(6), e5903 (2017).
pubmed: 28178129
pmcid: 5312986
doi: 10.1097/MD.0000000000005903
Kantara, C. et al. Methods for detecting circulating cancer stem cells (CCSCs) as a novel approach for diagnosis of colon cancer relapse/metastasis. Lab. Invest. 95(1), 100–112 (2015).
pubmed: 25347154
doi: 10.1038/labinvest.2014.133
Tang, L. et al. High expression of Anxa2 and Stat3 promote progression of hepatocellular carcinoma and predict poor prognosis. Pathol. Res. Pract. 215(6), 152386 (2019).
pubmed: 30935762
doi: 10.1016/j.prp.2019.03.015
Ding, Y. et al. Circular RNA profile of acute myeloid leukaemia indicates circular RNA Annexin A2 as a potential biomarker and therapeutic target for acute myeloid leukaemia. Am. J. Transl. Res. 12(5), 1683–1699 (2020).
pubmed: 32509169
pmcid: 7270033
Li, Y. et al. Bufalin induces mitochondrial dysfunction and promotes apoptosis of glioma cells by regulating Annexin A2 and DRP1 protein expression. Cancer Cell Int. 21(1), 424 (2021).
pubmed: 34376212
pmcid: 8353806
doi: 10.1186/s12935-021-02137-x
Khanal, T. et al. Protective role of intestinal bacterial metabolism against baicalin-induced toxicity in HepG2 cell cultures. J. Toxicol. Sci. 37(2), 363–371 (2012).
pubmed: 22467027
doi: 10.2131/jts.37.363
Kusakabe, Y. et al. Isolation and identification of the new baicalin target protein to develop flavonoid structure-based therapeutic agents. Bioorg. Med. Chem. 90, 117362 (2023).
pubmed: 37320992
doi: 10.1016/j.bmc.2023.117362
Adly Sadik, N., Ahmed Rashed, L. & Ahmed-Abd-El-Mawla, M. Circulating miR-155 and JAK2/STAT3 axis in acute ischemic stroke patients and its relation to post-ischemic inflammation and associated ischemic stroke risk factors. Int. J. Gen. Med. 14, 1469–1484 (2021).
pubmed: 33911894
pmcid: 8071708
doi: 10.2147/IJGM.S295939
Yang, X. et al. Profiling of genes associated with the murine model of oxygen-induced retinopathy. Mol. Vis. 19, 775–788 (2013).
pubmed: 23592914
pmcid: 3626293
Mori, K. et al. Preoperative heat shock protein 47 levels identify colorectal cancer patients with lymph node metastasis and poor prognosis. Oncol. Lett. 20(6), 333 (2020).
pubmed: 33123244
pmcid: 7583735
doi: 10.3892/ol.2020.12196
Verma, A. K. et al. Expression and correlation of cell-free cIAP-1 and cIAP-2 mRNA in breast cancer patients: A study from India. J. Oncol. 2020, 3634825 (2020).
pubmed: 32908506
pmcid: 7468656
doi: 10.1155/2020/3634825
Hu, X., Hu, X. & Wang, Q. Propofol induces apoptosis of hepatocellular carcinoma cells by upregulating miR-134 expression. Transl. Cancer Res. 10(6), 3004–3012 (2021).
pubmed: 35116608
pmcid: 8798760
doi: 10.21037/tcr-21-830
Kasahara, K. et al. myPresto/omegagene: a GPU-accelerated molecular dynamics simulator tailored for enhanced conformational sampling methods with a non-Ewald electrostatic scheme. Biophys. Physicobiol. 13, 209–216 (2016).
pubmed: 27924276
pmcid: 5060096
doi: 10.2142/biophysico.13.0_209
Sandeep, G. et al. AUDocker LE: A GUI for virtual screening with AUTODOCK Vina. BMC Res. Notes 4, 445 (2011).
pubmed: 22026969
pmcid: 3214202
doi: 10.1186/1756-0500-4-445
Trott, O. & Olson, A. J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 31(2), 455–461 (2010).
pubmed: 19499576
pmcid: 3041641
doi: 10.1002/jcc.21334
Hakobyan, D., Gerke, V. & Heuer, A. Modeling of annexin A2-membrane interactions by molecular dynamics simulations. PLoS One 12(9), e0185440 (2017).
pubmed: 28937994
pmcid: 5609761
doi: 10.1371/journal.pone.0185440
Réty, S. et al. The crystal structure of a complex of p11 with the annexin II N-terminal peptide. Nat. Struct. Biol. 6(1), 89–95 (1999).
pubmed: 9886297
doi: 10.1038/4965