Skip to main content

Advertisement

Log in

In vitro anti-cancer effect of marmesin by suppression of PI3K/Akt pathway in esophagus cancer cells

  • Original Article
  • Published:
Esophagus Aims and scope Submit manuscript

Abstract

Background

Marmesin, an important coumarin isolated from Broussonetia kazinoki, has been proposed to possess many pharmacological activities including anti-tumor activity. However, the anti-cancer effect of marmesin on esophageal cancer (EC) has not been characterized. The study aimed to explore the anti-cancer role of marmesin using EC cell lines in vitro.

Methods and results

Cell proliferation was evaluated by CCK-8 and Edu cell proliferation assays and apoptosis was detected by TUNEL assay. Western blot analysis was used to determine the expression of Ki67, proliferating cell nuclear antigen (PCNA), Bcl-2, Bax, phosphatidylinositol 3-kinase (PI3K), phosphoryrated-PI3K (p-PI3K), protein kinase B (Akt), and phosphoryrated-Akt (p-Akt). The mechanism of action of marmesin was analyzed using network pharmacology approach. Marmesin exhibited anti-proliferative effect against EC cells, which was further confirmed by the reduced expression of Ki67 and PCNA. Marmesin exerted pro-apoptotic activity on EC cells by downregulating Bcl-2 and upregulating Bax. According to the results from network pharmacology approach, we speculated that PI3K/Akt pathway may participate in the effect of marmesin on EC cells. Additionally, the PI3K/Akt pathway was suppressed by marmesin in EC cells. Moreover, forced expression of Akt reversed the inhibition of cell proliferation and induction of apoptosis induced by marmesin in EC cells.

Conclusions

Marmesin exerted anti-cancer activity in EC cells by inhibiting the PI3K/Akt pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30.

    Article  PubMed  Google Scholar 

  2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.

    Article  PubMed  Google Scholar 

  3. Sardana RK, Chhikara N, Tanwar B, Panghal A. Dietary impact on esophageal cancer in humans: a review. Food Funct. 2018;9(4):1967–77.

    Article  CAS  PubMed  Google Scholar 

  4. Smyth EC, Lagergren J, Fitzgerald RC, et al. Oesophageal cancer. Nat Rev Dis Primers. 2017;3:17048.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Shah MA. Update on metastatic gastric and esophageal cancers. J Clin Oncol. 2015;33(16):1760–9.

    Article  CAS  PubMed  Google Scholar 

  6. Ohashi S, Miyamoto S, Kikuchi O, Goto T, Amanuma Y, Muto M. Recent advances from basic and clinical studies of esophageal squamous cell carcinoma. Gastroenterology. 2015;149(7):1700–15.

    Article  PubMed  Google Scholar 

  7. Bai Y, Lin H, Fang Z, et al. Plasma microRNA-19a as a potential biomarker for esophageal squamous cell carcinoma diagnosis and prognosis. Biomark Med. 2017;11(5):431–41.

    Article  CAS  PubMed  Google Scholar 

  8. Domper Arnal MJ, Ferrández Arenas Á, Lanas AÁ. Esophageal cancer: risk factors, screening and endoscopic treatment in Western and Eastern countries. World J Gastroenterol. 2015;21(26):7933–43.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Kang X, Chen K, Li Y, Li J, D’Amico TA, Chen X. Personalized targeted therapy for esophageal squamous cell carcinoma. World J Gastroenterol. 2015;21(25):7648–58.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Thakur A, Singla R, Jaitak V. Coumarins as anticancer agents: a review on synthetic strategies, mechanism of action and SAR studies. Eur J Med Chem. 2015;101:476–95.

    Article  CAS  PubMed  Google Scholar 

  11. Cha JY, Kim YT, Kim HS, Cho YS. Antihyperglycemic effect of stem bark powder from paper mulberry (Broussonetia kazinoki Sieb.) in type 2 diabetic Otsuka Long-Evans Tokushima fatty rats. J Med Food. 2008;11(3):499–505.

    Article  CAS  PubMed  Google Scholar 

  12. Bae UJ, Jang HY, Lim JM, Hua L, Ryu JH, Park BH. Polyphenols isolated from Broussonetia kazinoki prevent cytokine-induced β-cell damage and the development of type 1 diabetes. Exp Mol Med. 2015;47(4):e160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ryu JH, Ahn H, Jin LH. Inhibition of nitric oxide production on LPS-activated macrophages by kazinol B from Broussonetia kazinoki. Fitoterapia. 2003;74(4):350–4.

    Article  CAS  PubMed  Google Scholar 

  14. Kim HS, Lim J, Lee DY, Ryu JH, Lim JS. Kazinol C from Broussonetia kazinoki activates AMP-activated protein kinase to induce antitumorigenic effects in HT-29 colon cancer cells. Oncol Rep. 2015;33(1):223–9.

    Article  CAS  PubMed  Google Scholar 

  15. Kim JS, Kim JC, Shim SH, et al. Chemical constituents of the root of Dystaenia takeshimana and their anti-inflammatory activity. Arch Pharm Res. 2006;29(8):617–23.

    Article  CAS  PubMed  Google Scholar 

  16. Kim JH, Kim JK, Ahn EK, et al. Marmesin is a novel angiogenesis inhibitor: regulatory effect and molecular mechanism on endothelial cell fate and angiogenesis. Cancer Lett. 2015;369(2):323–30.

    Article  CAS  PubMed  Google Scholar 

  17. Chen IS, Chang CT, Sheen WS, et al. Coumarins and antiplatelet aggregation constituents from Formosan Peucedanum japonicum. Phytochemistry. 1996;41(2):525–30.

    Article  CAS  PubMed  Google Scholar 

  18. Dong L, Xu WW, Li H, Bi KH. In vitro and in vivo anticancer effects of marmesin in U937 human leukemia cells are mediated via mitochondrial-mediated apoptosis, cell cycle arrest, and inhibition of cancer cell migration. Oncol Rep. 2018;39(2):597–602.

    CAS  PubMed  Google Scholar 

  19. Wang X, Shen Y, Wang S, et al. PharmMapper 2017 update: a web server for potential drug target identification with a comprehensive target pharmacophore database. Nucleic Acids Res. 2017;45(W1):W356–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Safran M, Chalifa-Caspi V, Shmueli O, et al. Human gene-centric databases at the Weizmann institute of science: GeneCards, UDB, CroW 21 and HORDE. Nucleic Acids Res. 2003;31(1):142–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Szklarczyk D, Gable AL, Nastou KC, et al. The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res. 2021;49(D1):D605–12.

    Article  CAS  PubMed  Google Scholar 

  22. Pink RC, Bailey TA, Iputo JE, Sammon AM, Woodman AC, Carter DR. Molecular basis for maize as a risk factor for esophageal cancer in a South African population via a prostaglandin E2 positive feedback mechanism. Nutr Cancer. 2011;63(5):714–21.

    Article  CAS  PubMed  Google Scholar 

  23. Znati M, Ben Jannet H, Cazaux S, Souchard JP, Harzallah Skhiri F, Bouajila J. Antioxidant, 5-lipoxygenase inhibitory and cytotoxic activities of compounds isolated from the Ferula lutea flowers. Molecules. 2014;19(10):16959–75.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Kim JH, Kim MS, Lee BH, et al. Marmesin-mediated suppression of VEGF/VEGFR and integrin β1 expression: its implication in non-small cell lung cancer cell responses and tumor angiogenesis. Oncol Rep. 2017;37(1):91–7.

    Article  PubMed  Google Scholar 

  25. Li P, Chen J, Wang J, et al. Systems pharmacology strategies for drug discovery and combination with applications to cardiovascular diseases. J Ethnopharmacol. 2014;151(1):93–107.

    Article  CAS  PubMed  Google Scholar 

  26. Boezio B, Audouze K, Ducrot P, Taboureau O. Network-based approaches in pharmacology. Mol Inform. 2017;36(10):1700048.

    Article  Google Scholar 

  27. Annovazzi L, Mellai M, Caldera V, Valente G, Tessitore L, Schiffer D. mTOR, S6 and AKT expression in relation to proliferation and apoptosis/autophagy in glioma. Anticancer Res. 2009;29(8):3087–94.

    CAS  PubMed  Google Scholar 

  28. Chappell WH, Steelman LS, Long JM, et al. Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health. Oncotarget. 2011;2(3):135–64.

    Article  PubMed  PubMed Central  Google Scholar 

  29. McCubrey JA, Steelman LS, Chappell WH, et al. Advances in targeting signal transduction pathways. Oncotarget. 2012;3(12):1505–21.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Falasca M. PI3K/Akt signalling pathway specific inhibitors: a novel strategy to sensitize cancer cells to anti-cancer drugs. Curr Pharm Des. 2010;16(12):1410–6.

    Article  CAS  PubMed  Google Scholar 

  31. Li B, Li J, Xu WW, et al. Suppression of esophageal tumor growth and chemoresistance by directly targeting the PI3K/AKT pathway. Oncotarget. 2014;5(22):11576–87.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Yu H, Jiang X, Jiang L, et al. Protocadherin 8 (PCDH8) inhibits proliferation, migration, invasion, and angiogenesis in esophageal squamous cell carcinoma. Med Sci Monit. 2020;26:e920665.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Yokota T, Serizawa M, Hosokawa A, et al. PIK3CA mutation is a favorable prognostic factor in esophageal cancer: molecular profile by next-generation sequencing using surgically resected formalin-fixed, paraffin-embedded tissue. BMC Cancer. 2018;18(1):826.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Mori R, Ishiguro H, Kimura M, et al. PIK3CA mutation status in Japanese esophageal squamous cell carcinoma. J Surg Res. 2008;145(2):320–6.

    Article  CAS  PubMed  Google Scholar 

  35. Wei L, Xu Z. Cross-signaling among phosphinositide-3 kinase, mitogen-activated protein kinase and sonic hedgehog pathways exists in esophageal cancer. Int J Cancer. 2011;129(2):275–84.

    Article  CAS  PubMed  Google Scholar 

  36. Kwak AW, Lee MJ, Lee MH, Yoon G, Cho SS, Chae JI, Shim JH. The 3-deoxysappanchalcone induces ROS-mediated apoptosis and cell cycle arrest via JNK/p38 MAPKs signaling pathway in human esophageal cancer cells. Phytomedicine. 2021;86:153564.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

QW performed the experiments and wrote the manuscript. SZ performed the experiments and analyzed the data. HW analyzed the data and contributed to bioinformatics analysis. QW designed and supervised this study. All authors read the manuscript and approved it for publication.

Corresponding author

Correspondence to Qingquan Wu.

Ethics declarations

Ethical statement

Not applicable.

Conflict of interest

None.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 590 KB)

Supplementary file2 (XLSX 10 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, Q., Zhong, S., Wu, H. et al. In vitro anti-cancer effect of marmesin by suppression of PI3K/Akt pathway in esophagus cancer cells. Esophagus 19, 163–174 (2022). https://doi.org/10.1007/s10388-021-00872-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10388-021-00872-8

Keywords

Navigation