Journal of Physiology & Pathology in Korean Medicine (동의생리병리학회지)

The Physiological Society of Korean Medicine and The Society of Pathology in Korean Medicine (대한동의생리학회·한의병리학회)
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Root Bark extract of Morus alba L. Suppressed the Migration and Invasion of HCT116 Human Colorectal Carcinoma Cells

HCT116 인체 대장암 세포주에서 상백피 추출물에 의한 전이 억제 효과

  • Park, Shin-Hyung (Department of Pathology, College of Korean Medicine, Dong-eui University) ;
  • Park, Hyun-Ji (Department of Pathology, College of Korean Medicine, Dong-eui University)
  • 박신형 (동의대학교 한의과대학 병리학교실) ;
  • 박현지 (동의대학교 한의과대학 병리학교실)
  • Received : 2021.08.24
  • Accepted : 2021.10.22
  • Published : 2021.10.25
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Abstract

The root bark of Morus alba L. (MA) used in traditional oriental medicine for the treatment of pulmonary diseases exerts various pharmacological activities including anticancer effects. In the current study, we investigated the effects of MA on the migration and invasion of colorectal carcinoma cells. Results from a transwell assay showed that the methylene chloride extract of MA (MEMA) suppressed the migration and invasion of HCT116 human colorectal carcinoma cells in a concentration-dependent manner. MEMA reduced both mRNA and protein levels of matrix metalloproteinase (MMP)-9, but did not suppress the expression of MMP-2 in HCT116 cells. As a molecular mechanism, MEMA inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs), including ERK, JNK and p38, in a dose-dependent manner. In addition, MEMA dephosphorylated both Src and signal transducer and activator of transcription 3 (STAT3) in HCT116 cells. Taken together, we demonstrate that MEMA suppressed the migration and invasion capacity of HCT116 human colorectal cancer cells by downregulation of MMP-9 and inactivation of both MAPKs and Src/STAT3 signaling pathway.

Keywords

Acknowledgement

본 연구는 한국연구재단의 우수신진연구(No. NRF-2021R1C1C100506211)의 사업비로 수행되었음.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-49. https://doi.org/10.3322/caac.21660
  2. National Cancer Information Center. Available from: https://www.cancer.go.kr
  3. Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet. 2019;394(10207):1467-80. https://doi.org/10.1016/s0140-6736(19)32319-0
  4. Markowitz SD, Bertagnolli MM. Molecular origins of cancer: Molecular basis of colorectal cancer. N Engl J Med. 2009;361(25):2449-60. https://doi.org/10.1056/NEJMra0804588
  5. American Cancer Society. Colorectal Cancer Facts & Figures 2020-2022. Atlanta: American Cancer Society Inc; 2020. p. 11.
  6. Rosen L, Jacobs I, Burkes R. Bevacizumab in colorectal cancer: current role in treatment and the potential of biosimilars. Target Oncol. 2017;12:599-610. https://doi.org/10.1007/s11523-017-0518-1
  7. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335-42. https://doi.org/10.1056/NEJMoa032691
  8. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351(4):337-45. https://doi.org/10.1056/NEJMoa033025
  9. Kopetz S, Grothey A, Yaeger R, Van Cutsem E, Desai J, Yoshino T, et al. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer. N Engl J Med. 2019;381(17):1632-43. https://doi.org/10.1056/NEJMoa1908075
  10. Martinelli E, Troiani T, Sforza V, Martini G, Cardone C, Vitiello PP, et al. Sequential HER2 blockade as effective therapy in chemorefractory, HER2 gene-amplified, RAS wildtype, metastatic colorectal cancer: learning from a clinical case. ESMO Open. 2018;3(1):e000299. https://doi.org/10.1136/esmoopen-2017-000299
  11. The Jointly Published Textbook Compilation Committee of Oriental College of Medicine Nationwide Department. Herbology. Seoul: Younglim press; 2004.
  12. Chan EW, Lye PY, Wong SK. Phytochemistry, pharmacology, and clinical trials of Morus alba. Chin J Nat Med. 2016;14(1):17-30. https://doi.org/10.3724/SP.J.1009.2016.00017
  13. Lim HJ, Jin HG, Woo ER, Lee SK, Kim HP. The root barks of Morus alba and the flavonoid constituents inhibit airway inflammation. J Ethnopharmacol. 2013;149(1):169-75. https://doi.org/10.1016/j.jep.2013.06.017
  14. Lee HJ, Ryu J, Park SH, Woo ER, Kim AR, Lee SK, et al. Effects of Morus alba L. and Natural Products Including Morusin on In Vivo Secretion and In Vitro Production of Airway MUC5AC Mucin. Tuberc Respir Dis (Seoul). 2014;77(2):65-72. https://doi.org/10.4046/trd.2014.77.2.65
  15. Kim HJ, Lee HJ, Jeong SJ, Lee HJ, Kim SH, Park EJ. Cortex Mori Radicis extract exerts antiasthmatic effects via enhancement of CD4(+)CD25(+)Foxp3(+) regulatory T cells and inhibition of Th2 cytokines in a mouse asthma model. J Ethnopharmacol. 2011;138(1):40-6, 2011. https://doi.org/10.1016/j.jep.2011.08.021
  16. El-Beshbishy HA, Singab AN, Sinkkonen J, Pihlaja K. Hypolipidemic and antioxidant effects of Morus alba L. (Egyptian mulberry) root bark fractions supplementation in cholesterol-fed rats. Life Sci. 2006;78(23):2724-33. https://doi.org/10.1016/j.lfs.2005.10.010
  17. Du J, He ZD, Jiang RW, Ye WC, Xu HX, But PPH. Antiviral flavonoids from the root bark of Morus alba L. Phytochemistry. 2003;62(8):1235-8. https://doi.org/10.1016/S0031-9422(02)00753-7
  18. Park SH, Chi GY, Eom HS, Kim GY, Hyun JW, Lee SJ, et al. Role of autophagy in apoptosis induction by methylene chloride extracts of Mori cortex in NCI-H460 human lung carcinoma cells. Int J Oncol. 2012;40(6):1929-40. https://doi.org/10.3892/ijo.2012.1386
  19. Min TR, Park HJ, Park MN, Kim B, Park SH. The root bark of Morus alba L. suppressed the migration of human non-smallcell lung cancer cells through inhibition of epithelial-mesenchymal transition mediated by STAT3 and Src. Int J Mol Sci. 2019;20(9):2244. https://doi.org/10.3390/ijms20092244
  20. Kikuchi T, Nihei M, Nagai H, Fukushi H, Tabata K, Suzuki T, et al. Albanol A from the root bark of Morus alba L. induces apoptotic cell death in HL60 human leukemia cell line. Chem Pharm Bull (Tokyo). 2010;58(4):568-71. https://doi.org/10.1248/cpb.58.568
  21. Eo HJ, Park JH, Park GH, Lee MH, Lee JR, Koo JS, et al. Anti-inflammatory and anti-cancer activity of mulberry (Morus alba L.) root bark. BMC Complement Med Ther. 2014;14:200. https://doi.org/10.1186/1472-6882-14-200
  22. Kwon YH, Bishayee K, Rahman A, Hong JS, Lim SS, Huh SO. Morus alba accumulates reactive oxygen species to initiate apoptosis via FOXO-caspase 3-dependent pathway in neuroblastoma cells. Mol Cells. 2015;38(7):630-7. https://doi.org/10.14348/MOLCELLS.2015.0030
  23. Park HJ, Chi GY, Choi YH, Park SH. The root bark of Morus alba L. regulates tumor-associated macrophages by blocking recruitment and M2 polarization of macrophages. Phytother Res. 2020;34(12):3333-44. https://doi.org/10.1002/ptr.6783
  24. Krakhmal NV, Zavyalova MV, Denisov EV, Vtorushin SV, Perelmuter VM. Cancer Invasion: Patterns and Mechanisms. Acta Naturae. 2015;7(2):17-28. https://doi.org/10.32607/20758251-2015-7-2-17-28
  25. Stamenkovic I. Matrix metalloproteinases in tumor invasion and metastasis. Semin Cancer Biol. 2000;10(6):415-33. https://doi.org/10.1006/scbi.2000.0379
  26. Braicu C, Buse M, Busuioc C, Drula R, Gulei D, Raduly L, et al. A Comprehensive Review on MAPK: A Promising Therapeutic Target in Cancer. Cancers (Basel). 2019;11(10):1618. https://doi.org/10.3390/cancers11101618
  27. Zhang S, Yu D. Targeting Src family kinases in anti-cancer therapies: Turning promise into triumph. Trends Pharmacol Sci. 2012;33(3):122-8. https://doi.org/10.1016/j.tips.2011.11.002
  28. Kamran MZ, Patil P, Gude RP. Role of STAT3 in Cancer Metastasis and Translational Advances. BioMed Res Int. 2013;2013:421821. https://doi.org/10.1155/2013/421821
  29. Cheng CY, Hsieh HL, Hsiao LD, Yang CM. PI3-K/Akt/JNK/NF-kappaB is essential for MMP-9 expression and outgrowth in human limbal epithelial cells on intact amniotic membrane. Stem Cell Res. 2012;9(1):9-23. https://doi.org/10.1016/j.scr.2012.02.005
  30. Simon C, Simon M, Vucelic G, Hicks MJ, Plinkert PK, Koitschev A, et al. The p38 SAPK pathway regulates the expression of the MMP-9 collagenase via AP-1-dependent promoter activation. Exp Cell Res. 2001;271(2):344-55. https://doi.org/10.1006/excr.2001.5374
  31. Cho A, Graves J, Reidy MA. Mitogen-activated protein kinases mediate matrix metalloproteinase-9 expression in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2000;20(12):2527-32. https://doi.org/10.1161/01.ATV.20.12.2527
  32. Jia ZH, Jia Y, Guo FJ, Chen J, Zhang XW, Cui MH. Phosphorylation of STAT3 at Tyr705 regulates MMP-9 production in epithelial ovarian cancer. PLoS One. 2017;12(8):e0183622. https://doi.org/10.1371/journal.pone.0183622
  33. Liu JF, Chen PC, Chang TM, Hou CH. Thrombospondin-2 stimulates MMP-9 production and promotes osteosarcoma metastasis via the PLC, PKC, c-Src and NF-kappaB activation. J Cell Mol Med. 2020;24(21):12826-39. https://doi.org/10.1111/jcmm.15874
  34. Schindler C, Levy DE, Decker T. JAK-STAT Signaling: From Interferons to Cytokines. J Biol Chem. 2007;282(28):20059-63. https://doi.org/10.1074/jbc.R700016200
  35. Lin WL, Lai DY, Lee YJ, Chen NF, Tseng TH. Antitumor progression potential of morusin suppressing STAT3 and NFB in human hepatoma SK-Hep1 cells. Toxicol Lett. 2015;232(2):490-8. https://doi.org/10.1016/j.toxlet.2014.11.031
  36. Prasad S, Yadav VR, Sung B, Reuter S, Kannappan R, Deorukhkar A, et al. Ursolic Acid Inhibits Growth and Metastasis of Human Colorectal Cancer in an Orthotopic Nude Mouse Model by Targeting Multiple Cell Signaling Pathways: Chemosensitization with Capecitabine. Clin Cancer. 2012;18(18):4942-53. https://doi.org/10.1158/1078-0432.CCR-11-2805
  37. Liu P, Du R, Yu X. Ursolic Acid Exhibits Potent Anticancer Effects in Human Metastatic Melanoma Cancer Cells (SK-MEL-24) via Apoptosis Induction, Inhibition of Cell Migration and Invasion, Cell Cycle Arrest, and Inhibition of Mitogen-Activated Protein Kinase (MAPK)/ERK Signaling Pathway. Med Sci Monit. 2019;25:1283-90. https://doi.org/10.12659/msm.913069
  38. Mosesson Y, Yarden Y. Oncogenic growth factor receptors: implications for signal transduction therapy. Semin Canc Biol. 2014;14(4):262-70. https://doi.org/10.1016/j.semcancer.2004.04.005
  39. Park HJ, Min TR, Chi GY, Choi YH, Park SH. Induction of apoptosis by morusin in human non-small cell lung cancer cells by suppression of EGFR/STAT3 activation. Biochem Biophys Res Commun. 2018;505(1):194-200. https://doi.org/10.1016/j.bbrc.2018.09.085