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Anticancer Activity of Holothuria Leucospilota-Derived Saponin on MNK45 Gastric Cancer Cell via Upregulation of CDH1 Hub Gene

Articles in Press

Document Type : Original Article(s)

Authors

1 Department of Biological Science and Technology, Faculty of Nano- and Bio-Science and Technology, Persian Gulf University, Bushehr, Iran

2 Persian Gulf Research Institute, Persian Gulf University, Bushehr, Iran

10.30476/mejc.2024.100200.1976

Abstract

Background: The treatment of gastric cancer (GC) is still quite challenging. Yet, marine invertebrates have been found to produce a wide range of anticancer bioactive compounds that show promise in fighting cancer. The present study aimed to evaluate whether saponin derived from Holothuria leucospilata (H. Leucospilota), a species of sea cucumber, possesses anti-cancer activity against GC cells.
Method: In this experimental study, the cytotoxic effect of H. Leucospilota-derived n-butanol fraction saponins (HLBS) sourced from the Persian Gulf on MNK45 GC cells was evaluated through tetrazolium salt and colony formation assays. The effect of HLBS on MNK45 cell migration, cell cycle, and apoptosis was assessed using a scratch assay, and flow cytometry, respectively. Hub genes of GC were identified through bioinformatics analysis. The effects of HLBS on the expression of the two top-ranked GC hub genes were measured using real-time polymerase chain reaction. Comparisons between groups were performed using the ANOVA test by GraphPad Prism software at the statistically significant P-value <0.05.
Results: HLBS with an IC50 concentration of 75 μg/ml at 48 hours resulted in a significant decrease in cell viability, clonogenic ability (46.63% reduction, P < 0.01), and migration of MNK45 cells (74.5% reduction, P < 0.01). Moreover, HLBS led to an increase of approximately 21% and 13% in the S-phase and apoptotic cell populations, respectively. HLBS also upregulated the expression of CDH1, as a highly ranked hub gene associated with GC (P < 0.05).
Conclusion: The inhibitory effect of HLBS on MNK45 cells suggests HLBS as a candidate for further drug discovery programs in GC research, and paves the way to introduce new anti-cancer HLBS synthetic derivatives.

Highlights

Khadijeh Sadegh (PubMed)

Amirhossein Ahmadi (PubMed)

Keywords

Main Subjects

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination, and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.30476/mejc.2024.100200.1976

References
  1. Morgan E, Arnold M, Camargo MC, Gini A, Kunzmann AT, Matsuda T, et al. The current and future incidence and mortality of gastric cancer in 185 countries, 2020-40: A population-based modelling study. EClinicalMedicine. 2022;47:101404. doi: 10.1016/j.eclinm.2022.101404.
  2. Sadegh K, Ahmadi A. Hub genes and pathways in gastric cancer: A comparison between studies that used normal tissues adjacent to the tumour and studies that used healthy tissues as calibrator. IET Syst Biol. 2023;17(3):131-41. doi: 10.1049/syb2.12065.
  3. Lin X, Zhao Y, Song WM, Zhang B. Molecular classification and prediction in gastric cancer. Comput Struct Biotechnol J. 2015;13:448-58. doi: 10.1016/j.csbj.2015.08.001.
  4. Mottaghi-Dastjerdi N, Ghorbani A, Montazeri H, Guzzi PH. A systems biology approach to pathogenesis of gastric cancer: gene network modeling and pathway analysis. BMC Gastroenterol. 2023;23(1):248. doi: 10.1186/s12876-023-02891-4.
  5. Han C, Jin L, Ma X, Hao Q, Lin H, Zhang Z. Identification of the hub genes RUNX2 and FN1 in gastric cancer. Open Med (Wars). 2020;15(1):403-12. doi: 10.1515/med-2020-0405.
  6. Lu XQ, Zhang JQ, Zhang SX, Qiao J, Qiu MT, Liu XR, et al. Identification of novel hub genes associated with gastric cancer using integrated bioinformatics analysis. BMC Cancer. 2021;21(1):697. doi: 10.1186/s12885-021-08358-7.
  7. Hsiao CT, Cheng HW, Huang CM, Li HR, Ou MH, Huang JR, et al. Fibronectin in cell adhesion and migration via N-glycosylation. Oncotarget. 2017;8(41):70653-68. doi: 10.18632/oncotarget.19969.
  8. Shenoy S. CDH1 (E-cadherin) mutation and gastric cancer: genetics, molecular mechanisms and guidelines for management. Cancer Manag Research. 2019;11:10477. doi: 10.2147/CMAR.S208818.
  9. Orditura M, Galizia G, Sforza V, Gambardella V, Fabozzi A, Laterza MM, et al. Treatment of gastric cancer. World J Gastroenterol. 2014;20(7):1635-49.doi: 10.3748/wjg.v20.i7.1635.
  10. Sitarz R, Skierucha M, Mielko J, Offerhaus GJA, Maciejewski R, Polkowski WP. Gastric cancer: epidemiology, prevention, classification, and treatment. Cancer Manag Res. 2018;10:239. doi: 10.2147/CMAR.S149619.
  11. Thrift AP, El-Serag HB. Burden of gastric cancer. Clin Gastroenterol Hepatol. 2020;18(3):534-42. doi: https://doi.org/10.1016/j.cgh.2019.07.045.
  12. Liu YQ, Wang XL, He DH, Cheng YX. Protection against chemotherapy-and radiotherapy-induced side effects: A review based on the mechanisms and therapeutic opportunities of phytochemicals. Phytomedicine. 2021;80:153402. doi: 10.1016/j.phymed.2020.153402.
  13. Law JW, Law LN, Letchumanan V, Tan LT, Wong SH, Chan KG, et al. Anticancer drug discovery from microbial sources: the unique mangrove streptomycetes. 2020;25(22):5365. doi: 10.3390/molecules25225365.
  14. Patra S, Praharaj PP, Panigrahi DP, Panda B, Bhol CS, Mahapatra KK, et al. Bioactive compounds from marine invertebrates as potent anticancer drugs: the possible pharmacophores modulating cell death pathways. Mol Biol Rep. 2020;47(9):7209-28. doi: 10.1007/s11033-020-05709-8.
  15. Adrian TE, Collin P. The anti-cancer effects of frondoside A. Mar drugs. 2018;16(2):64. doi: 10.3390/md16020064.
  16. Pangestuti R, Arifin Z. Medicinal and health benefit effects of functional sea cucumbers. J Tradit Complement Med. 2018;8(3):341-51. doi: 10.1016/j.jtcme.2017.06.007.
  17. Yu S, Ye X, Huang H, Peng R, Su Z, Lian XY, et al. Bioactive sulfated saponins from sea cucumber Holothuria moebii. Planta Med. 2015;81(2):152-9. doi: 10.1055/s-0034-1383404.
  18. Luparello C, Ragona D, Asaro DML, Lazzara V, Affranchi F, Celi M, et al. Cytotoxic potential of the coelomic fluid extracted from the sea cucumber Holothuria tubulosa against triple-negative MDA-MB231 breast cancer cells. Biology. 2019;8(4):76. doi: 10.3390/biology8040076.
  19. Podolak I, Grabowska K, Sobolewska D, Wróbel-Biedrawa D, Makowska-Wąs J, Galanty A. Saponins as cytotoxic agents: an update (2010–2021). Part II—Triterpene saponins. Phytochem Rev. 2023;22:113-67. https://doi.org/10.1007/s11101-022-09830-3.
  20. Khotimchenko Y. Pharmacological potential of sea cucumbers. Int J Mol Sci. 2018;19(5):1342. doi: 10.3390/ijms19051342.
  21. Malaiwong N, Chalorak P, Jattujan P, Manohong P, Niamnont N, Suphamungmee W, et al. Anti-Parkinson activity of bioactive substances extracted from Holothuria leucospilota. Biomed Pharmacother. 2019;109:1967-77. doi: 10.1016/j.biopha.2018.11.063.
  22. Moghadam FD, Baharara J, Balanezhad SZ, Jalali M, Amini E. Effect of Holothuria leucospilota extracted saponin on maturation of mice oocyte and granulosa cells. Res Pharm Sci. 2016;11(2):130-7.
  23. Soltani M, Parivar K, Baharara J, Kerachian MA, Asili J. Hemolytic and cytotoxic properties of saponin purified from Holothuria leucospilota sea cucumber. Rep Biochem Mol Biol. 2014;3(1):43-50.
  24. Siragusa M, Dall’Olio S, Fredericia PM, Jensen M, Groesser T. Cell colony counter called CoCoNut. PloS one. 2018;13:e0205823. doi: 10.1371/journal.pone.0205823.
  25. Justus CR, Leffler N, Ruiz-Echevarria M, Yang LV. In vitro cell migration and invasion assays. J Vis Exp. 2014;(88):51046. doi: 10.3791/51046.
  26. Brauchle E, Thude S, Brucker SY, Schenke-Layland K. Cell death stages in single apoptotic and necrotic cells monitored by Raman microspectroscopy. Sci Rep. 2014;4:1-9. doi: 10.1038/srep04698.
  27. Kartikaningsih H, A’yunin Q, Soeprijanto A, Arifin NB, editors. Black sea cucumber (Holothuria atra) ethanol extract as Edwardsiella tarda antibacterial. AIP Conf. Proc. 2019; 060010-1–060010-9. doi:10.1063/1.5061919.
  28. Plaskova A, Mlcek J. New insights of the application of water or ethanol-water plant extract rich in active compounds in food. Front Nutr. 2023;10:1118761. doi: 10.3389/fnut.2023.1118761.
  29. Soltani M, Parivar K, Baharara J, Kerachian MA, Asili J. Putative mechanism for apoptosis-inducing properties of crude saponin isolated from sea cucumber (Holothuria leucospilota) as an antioxidant compound. Iran J Basic Med Sci. 2015;18(2):180-7.
  30. Shushizadeh MR. Phytochemical analysis of Holothuria leucospilota, a sea cucumber from Persian Gulf. Res Pharm Sci. 2019;14(5):432-40. doi: 10.4103/1735-5362.268204.
  31. Khaledi M, Moradipoodeh B, Moradi R, Baghbadorani MA, Mahdavinia M. Antiproliferative and proapoptotic activities of Sea Cucumber H. Leucospilota extract on breast carcinoma cell line (SK-BR-3). Mol Biol Rep. 2022;49(2):1191-200. doi: 10.1007/s11033-021-06947-0.
  32. Pranweerapaiboon K, Noonong K, Apisawetakan S, Sobhon P, Chaithirayanon K. Methanolic extract from sea cucumber, holothuria scabra, induces apoptosis and suppresses metastasis of PC3 prostate cancer cells modulated by MAPK signaling pathway. J Microbiol Biotechnol. 2021;31(6):775-83. doi: 10.4014/jmb.2103.03034.
  33. Silchenko AS, Kalinovsky AI, Avilov SA, Andryjaschenko PV, Dmitrenok PS, Yurchenko EA, et al. Cladolosides O, P, P1-P3 and R, triterpene glycosides with two novel types of carbohydrate chains from the sea cucumber Cladolabes schmeltzii. Inhibition of cancer cells colony formation and its synergy with radioactive irradiation. Carbohydr Res. 2018;468:73-9. doi: 10.1016/j.carres.2018.08.004.
  34. Liu F, Tang L, Tao M, Cui C, He D, Li L, et al. Stichoposide C exerts anticancer effects on ovarian cancer by inducing autophagy via inhibiting AKT/mTOR pathway. Onco Targets Ther. 2022;15:87. doi: 10.2147/OTT.S340556.
  35. Baharara J, Amini E, Nikdel N, Salek-Abdollahi F. The cytotoxicity of dacarbazine potentiated by sea cucumber saponin in resistant B16F10 melanoma cells through apoptosis induction. Avicenna J Med Biotechnol. 2016;8(3):112.
  36. Cui H, Bashar MA, Rady I, El-Naggar HA, El-Maoula A, Lamiaa M, et al. Antiproliferative activity, proapoptotic effect, and cell cycle arrest in human cancer cells of some marine natural product extract. Oxid Med Cell Longev. 2020;2020:7948705 doi: 10.1155/2020/7948705.
  37. Ru R, Guo Y, Mao J, Yu Z, Huang W, Cao X, et al. Cancer cell inhibiting sea cucumber (holothuria leucospilota) protein as a novel anti-cancer drug. Nutrients. 2022;14(4):786. doi: 10.3390/nu14040786.
  38. Sun C, Yuan Q, Wu D, Meng X, Wang B. Identification of core genes and outcome in gastric cancer using bioinformatics analysis. Oncotarget. 2017;8(41):70271. doi: 10.18632/oncotarget.20082.
  39. Zhou Y, Cao G, Cai H, Huang H, Zhu X. The effect and clinical significance of FN1 expression on biological functions of gastric cancer cells. Cell Mol Biol (Noisy-le-grand). 2020;66(5):191-8.
  40. Cai X, Liu C, Zhang TN, Zhu YW, Dong X, Xue P. Down‐regulation of FN1 inhibits colorectal carcinogenesis by suppressing proliferation, migration, and invasion. J cell Biochem. 2018;119(6):4717-28.
  41. Zhou Y, Shu C, Huang Y. Fibronectin promotes cervical cancer tumorigenesis through activating FAK signaling pathway. J Cell Biochem. 2019;120(7):10988-97. doi: 10.1002/jcb.28282.
  42. Sun Y, Zhao C, Ye Y, Wang Z, He Y, Li Y, et al. High expression of fibronectin 1 indicates poor prognosis in gastric cancer. Oncol Lett. 2020;19(1):93-102. doi: 10.3892/ol.2019.11088.
  43. Melo S, Figueiredo J, Fernandes MS, Gonçalves M, Morais-de-Sá E, Sanches JM, et al. Predicting the functional impact of CDH1 missense mutations in hereditary diffuse gastric cancer. Int J Mol Sci. 2017;18(2):2687. doi: 10.3390/ijms18122687.
  44. Kheirollahi M, Saneipour M, Tabatabaiefar MA, Zeinalian M, Minakari M, Moridnia A. New variants in the CDH1 gene in Iranian families with hereditary diffuse gastric cancer. Middle East J Cancer. 2020;11(4):493-501. doi: 10.30476/mejc.2020.81478.1016.
  45. Kang KA, Kim HS, Kim DH, Hyun JW. The role of a ginseng saponin metabolite as a DNA methyltransferase inhibitor in colorectal cancer cells. Int J Oncol. 2013;43(1):228-36. doi: 10.3892/ijo.2013.1931.
Middle East Journal of Cancer

Articles in Press, Accepted Manuscript
Available Online from 16 April 2024
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