Baicalein blocked gastric cancer cell proliferation and invasion through modulated platelet type 12-lipoxygenase

Document Type : Original Article

Authors

1 Cancer Research Center, Yanbian University Medical College, Key Laboratory of Pathobiology (Yanbian University), State Ethnic Affairs Commission, Research and Innovation Group of Yanbian University, Yanji 133002, China

2 Department of Anatomy, School of Basic Medicine, Binzhou Medical University, Yantai, 264000, China

3 Department of Pathology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000, Zhejiang, China

4 Chifeng Municipal Hospital, Chifeng, 024000, Inner Mongolia, China

5 Department of Internal Medicine, Yanbian University Hospital, Yanji 133000, China

Abstract

Objective(s): Baicalein (BAI) is one of the main ingredients of Scutellaria baicalensis georgi. Its pharmacological effects have been widely reported in various cancers. However, the specific molecular mechanism of BAI in gastric cancer (GC) has not been defined. This study investigates BAI’s inhibitory effect on gastric cancer and its potential mechanisms.
Materials and Methods: Gastric normal (GES-1 cells) and cancer cells (MKN-74 and MGC-803 cells) were treated with different concentrations of BAI. Cell proliferation and migration were assessed by MTT, colony formation, wound healing, and transwell assays. Flow cytometry and Hoechst 33342 staining were used to detect the cell apoptosis. IF and WB tests were employed to detect EMT-related protein. Finally, the anti-tumor effects of BAI were verified in in vivo xenograft models. 
Results: Our results show that the cell viability of MKN-74 and MGC-803 cells was significantly decreased in a time- and dose-dependent manner after BAI treatment by MTT assay. The expression levels of p12-LOX genes, which were determined by quantitative RT-PCR and WB, in MKN-74 cells were higher than those in GES-1 cells. As shown by the wound healing assay and Transwell assay, the treatment with BAI also significantly suppressed GC cell migration and invasion. Besides, BAI inhibited the phosphorylation of ERK1/2 and MEK1/2 in GC cells, as revealed by WB. Furthermore, BAI significantly inhibited tumor growth capacities in a xenograft model. 
Conclusion: BAI shows a significant anti-tumor effect and inhibition on tumor cell migration and invasion, which is probably through regulation of p12-LOX modulated epithelial-mesenchymal transformation.

Keywords

Main Subjects

References

1. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin 2023;73:17-48. 
2. Biagioni A, Skalamera I, Peri S, Schiavone N, Cianchi F, Giommoni E, et al. Update on gastric cancer treatments and gene therapies. Cancer Metastasis Rev 2019;38:537-548.
3. Akhmetkaliyev A, Alibrahim N, Shafiee D, Tulchinsky E. EMT/MET plasticity in cancer and Go-or-Grow decisions in quiescence: the two sides of the same coin? Mol Cancer 2023;22:90-105.
4. Gundamaraju R, Lu W, Paul MK, Jha NK, Gupta PK, Ojha S, et al. Autophagy and EMT in cancer and metastasis: Who controls whom? Biochim Biophys Acta Mol Basis Dis 2022;1868:166431.
5. F. Peng, X. Xie and C. Peng. Chinese herbal medicine-based cancer therapy: Novel anticancer agents targeting MicroRNAs to regulate tumor growth and metastasis. Am J Chin Med 2019;47:1711-1735.
6. Morshed AKMH, Paul S, Hossain A, Basak T, Hossain MS, Hasan MM, et al. Baicalein as promising anticancer agent: A comprehensive analysis on molecular mechanisms and therapeutic perspectives. Cancers (Basel) 2023;15:2128-2155.
7. M. Wang, S. Qiu and J. Qin. Baicalein induced apoptosis and autophagy of undifferentiated thyroid cancer cells by the ERK/PI3K/Akt pathway. Am J Transl Res 2019;11:3341-3352.
8. Huang L, Peng B, Nayak Y, Wang C, Si F, Liu X, et al. Baicalein and baicalin promote melanoma apoptosis and senescence via metabolic inhibition. Front Cell Dev Biol. 2020; 8: 836-852.
9. Hua F, Xiao YY, Qu XH, Li SS, Zhang K, Zhou C, et al. Baicalein sensitizes triple negative breast cancer MDA-MB-231 cells to doxorubicin via autophagy-mediated down-regulation of CDK1. Mol Cell Biochem 2023;478:1519-1531.
10. Chuang TC, Fang GS, Hsu SC, Lee YJ, Shao WS, Wang V, et al. Baicalein suppresses HER2-mediated malignant transformation of HER2-overexpressing ovarian cancer cells by downregulating HER2 gene expression. Environ Toxicol 2023;38:1609-1617.
11. Piao YS, Du YC, Oshima H, Jin JC, Nomura M, Yoshimoto T, et al. Platelet-type 12-lipoxygenase accelerates tumor promotion of mouse epidermal cells through enhancement of cloning efficiency. Carcinogenesis 2008;29:440-447.
12. Ma X, Yan W, Dai Z, Gao X, Ma Y, Xu Q, et al. Baicalein suppresses metastasis of breast cancer cells by inhibiting EMT via downregulation of SATB1 and Wnt/beta-catenin pathway. Drug Des Devel Ther 2016:10:1419-1441.
13. Coffey MJ, Jarvis GE, Gibbins JM, Coles B, Barrett NE, Wylie OR, et al. Platelet 12-lipoxygenase activation via glycoprotein VI: involvement of multiple signaling pathways in agonist control of H(P)ETE synthesis. Cir Res 2004;94:1598-1605.
14. Kumar R, Singh AK, Kumar M, Shekhar S, Rai N, Kaur P, et al. Serum 5-LOX: A progressive protein marker for breast cancer and new approach for therapeutic target. Carcinogenesis 2016;37:912-917.
15. Qu Y, Wen Z, Mi S, Chen P, Wang J, Jia Y, et al. 12-lipoxygenase promotes tumor progress by TGF-β1-mediated epithelial to mesenchymal transition and predicts poor prognosis in esophageal squamous cell carcinoma. Cancer Manag Res 2019;11:8303-8313.
16. Nosaka T, Murata Y, Takahashi K, Naito T, Ofuji K, Matsuda H, et al. Hepatocellular carcinoma progression promoted by 5-lipoxygenase activity in CD163(+) tumor-associated macrophages. Biomed Pharmacother 2023;162:114592.
17. Sarsour EH, Son JM, Kalen AL, Xiao W, Du J, Alexander MS, et al. Arachidonate 12-lipoxygenase and 12-hydroxyeicosatetraenoic acid contribute to stromal aging-induced progression of pancreatic cancer. J Biol Chem 2020;295:6946-6957.
18. Wu Y, Mao F, Zuo X, Moussalli MJ, Elias E, Xu W, et al. 15-LOX-1 suppression of hypoxia-induced metastatic phenotype and HIF-1alpha expression in human colon cancer cells. Cancer Med 2014;3:472-484.
19. Chen FL, Wang XZ, Li JY, Yu JP, Huang CY, Chen ZX. 12-lipoxygenase induces apoptosis of human gastric cancer AGS cells via the ERK1/2 signal pathway. Dig Dis Sci 2008;53:181-187.
20. Zhao X, Qu J, Liu X, Wang J, Ma X, Zhao X, et al. Baicalein suppress EMT of breast cancer by mediating tumor-associated macrophages polarization. Am J Cancer Res. 2018;8:1528-1540.
21. Qiao D, Xing J, Duan Y, Wang S, Yao G, Zhang S, et al. The molecular mechanism of baicalein repressing progression of gastric cancer mediating miR-7/FAK/AKT signaling pathway. Phytomedicine 2022;100:154046.
22. Baek SH, Ko JH, Lee JH, Kim C, Lee H, Nam D, et al. Ginkgolic acid inhibits invasion and migration and TGF-beta-induced EMT of lung cancer cells through PI3K/Akt/mTOR inactivation. J Cellular Physiol 2017;232:346-354.
23. Ke M, Zhang Z, Xu B, Zhao S, Ding Y, Wu X, et al. Baicalein and baicalin promote antitumor immunity by suppressing PD-L1 expression in hepatocellular carcinoma cells. Int Immunopharmacol 2019;75:105824.
24. Tuli HS, Bhushan S, Kumar A, Aggarwal P, Sak K, Ramniwas S, et al. Autophagy induction by scutellaria flavones in cancer: Recent advances. Pharmaceuticals (Basel) 2023;16:302-320.
25. Zhang X, Ruan Q, Zhai Y, Lu D, Li C, Fu Y, et al. Baicalein inhibits non-small-cell lung cancer invasion and metastasis by reducing ezrin tension in inflammation microenvironment. Cancer Sci 2020;111:3802-3812.
26. Chen X, Clement M, Hicks MJ, Sarkar P, Gaber MW, Man TK. LOX upregulates FAK phosphorylation to promote metastasis in osteosarcoma. Genes Dis 2022;10:254-266.
27. Doucet MS, Jougleux JL, Poirier SJ, Cormier M, Léger JL, Surette ME, et al. Identification of peracetylated quercetin as a selective 12-lipoxygenase pathway inhibitor in human platelets. mol. Pharmacol 2019;11:139-150.
28. Bhat AA, Thapa R, Afzal O, Agrawal N, Almalki WH, Kazmi I, et al. The pyroptotic role of Caspase-3/GSDME signalling pathway among various cancer: A review. Int J Biol Macromol 2023;242:124832.
29. Zhang ZH, Li MY, Wang Z, Zuo HX, Wang JY, Xing Y, et al. Convallatoxin promotes apoptosis and inhibits proliferation and angiogenesis through crosstalk between JAK2/STAT3 (T705) and mTOR/STAT3 (S727) signaling pathways in colorectal cancer. Phytomedicine 2020;68:153172.
30. Yuan K, Xie K, Lan T, Xu L, Chen X, Li X, et al. TXNDC12 promotes EMT and metastasis of hepatocellular carcinoma cells via activation of β-catenin. Cell Death  Differ 2020;27:1355-1368.
31. Sabouni E, Nejad MM, Mojtabavi S, Khoshduz S, Mojtabavi M, Nadafzadeh N, et al. Unraveling the function of epithelial-mesenchymal transition (EMT) in colorectal cancer: Metastasis, therapy response, and revisiting molecular pathways. Biomed Pharmacother 2023;160:114395.
32. Jiang M, Wu YL, Li X, Zhang Y, Xia KL, Cui BW, et al. Oligomeric proanthocyanidin derived from grape seeds inhibited NF-kB signaling in activated HSC: Involvement of JNK/ERK MAPK and PI3K/Akt pathways. Biomed Pharmacother 2017;93:674-680.
33. L. Nguyen, Y. Song and S. Cho. Baicalein inhibits epithelial to mesenchymal transition via downregulation of Cyr61 and LOXL-2 in MDA-MB231 breast cancer cells. Mol Cells 2016;39:909-914.
34. Fu L, Chen S, He G, Chen Y, Liu B. Targeting extracellular signal-regulated protein kinase 1/2 (ERK1/2) in cancer: An update on pharmacological small-molecule inhibitors. J Med Chem 2022;65:13561-13573.
35. Luo YH, Zhang L, Wang MY, Fang J, Xia JY, Yu XL. Anti-cancer effects of baicalein on cervical carcinoma cells through down-regulation of the ERK/p38/MAPK pathway. J Biol Regul Homeost Agents 2021;35:945-952.
36. Park YG, Choi J, Jung HK, Kim B, Kim C, Park SY, et al. Baicalein inhibits tumor progression by inhibiting tumor cell growth and tumor angiogenesis. Oncol Rep 2017;38:3011-3018.
37. Jonker DM, Visser SA, van der Graaf PH, Voskuyl RA, Danhof M. Towards a mechanism-based analysis of pharmacodynamic drug-drug interactions in vivo. Pharmacol Ther 2005;106:1-18.
38. Langeh U, Kumar V, Singh C, Singh A. Drug-herb combination therapy in cancer management. Mol Biol Rep 2022;49:11009-11024.
39. Li P, Hu J, Shi B, Tie J. Baicalein enhanced cisplatin sensitivity of gastric cancer cells by inducing cell apoptosis and autophagy via Akt/mTOR and Nrf2/Keap 1 pathway. Biochem Biophys Res Commun 2020;531:320-327.
40. Chen F, Zhuang M, Zhong C, Peng J, Wang X, Li J, et al. Baicalein reverses hypoxia-induced 5-FU resistance in gastric cancer AGS cells through suppression of glycolysis and the PTEN/Akt/HIF-1α signaling pathway. Oncol Rep 2015;33:457-463.
 
Iranian Journal of Basic Medical Sciences
Volume 27, Issue 12
December 2024
Pages 1574-1582

Files

Share

How to cite

Statistics