Skip to main content
SpringerLink
Log in

Moscatilin inhibits epithelial-to-mesenchymal transition and sensitizes anoikis in human lung cancer H460 cells

  • Original Paper
  • Published:
Journal of Natural Medicines Aims and scope Submit manuscript

Abstract

Metastasis in lung cancer has been recognized as an important cause of high mortality. Resistance to anoikis and the epithelial-to-mesenchymal transition (EMT) are critical factors for the successful spread of cancer cells. Compounds that suppress these features of cancer cells should be potentially active for anti-metastasis approaches. We have demonstrated for the first time that moscatilin, at its non-toxic concentrations to lung cancer cells and human normal keratinocytes, significantly decreases lung cancer cell survival in the detached condition, and suppresses the formation of tumors in an anchorage-independent growth assay. Furthermore, we found that moscatilin significantly decreased the activated level of survival proteins, namely ERK and Akt. In addition, moscatilin down-regulated cavelolin-1 (Cav-1), leading to a reduction in anti-apoptotic Mcl-1 protein. In terms of EMT, treatment of the cells with moscatilin significantly suppressed mesenchymal cell markers, namely vimentin, Slug, and Snail. These results indicate that moscatilin inhibited anoikis resistance in lung cancer cells via survival suppression, Cav-1 down-regulation, and inhibition of EMT. The compound could therefore be beneficial for the treatment and prevention of lung cancer metastasis.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

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

Similar content being viewed by others

References

  1. Zhang Z, Han L, Cao L, Liang X, Liu Y, Liu H, Du J, Qu Z, Zhu C, Liu S, Li H, Sun W (2008) Aggregation formation mediated anoikis resistance of BEL7402 hepatoma cells. Folia Histochem Cytobiol 46:331–336

    Article  CAS  PubMed  Google Scholar 

  2. Yongsanguanchai N, Pongrakhananon V, Mutirangura A, Rojanasakul Y, Chanvorachote P (2015) Nitric oxide induces cancer stem cell-like phenotypes in human lung cancer cells. Am J Physiol Cell Physiol 308:C89–100

    Article  CAS  PubMed  Google Scholar 

  3. Winitthana T, Lawanprasert S, Chanvorachote P (2014) Triclosan potentiates epithelial-to-mesenchymal transition in anoikis-resistant human lung cancer cells. PLoS One 9:e110851

    Article  PubMed Central  PubMed  Google Scholar 

  4. Wheelock MJ, Shintani Y, Maeda M, Fukumoto Y, Johnson KR (2008) Cadherin switching. J Cell Sci 121:727–735

    Article  CAS  PubMed  Google Scholar 

  5. Wang ZL, Fan ZQ, Jiang HD, Qu JM (2013) Selective Cox-2 inhibitor celecoxib induces epithelial-mesenchymal transition in human lung cancer cells via activating MEK-ERK signaling. Carcinogenesis 34:638–646

    Article  CAS  PubMed  Google Scholar 

  6. Voulgari A, Pintzas A (2009) Epithelial–mesenchymal transition in cancer metastasis: mechanisms, markers and strategies to overcome drug resistance in the clinic. Biochim Biophys Acta 1796:75–90

    CAS  PubMed  Google Scholar 

  7. Vega S, Morales AV, Ocana OH, Valdes F, Fabregat I, Nieto MA (2004) Snail blocks the cell cycle and confers resistance to cell death. Genes Dev 18:1131–1143

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Valastyan S, Weinberg RA (2011) Tumor metastasis: molecular insights and evolving paradigms. Cell 147:275–292

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Tanagornmeatar K, Chaotham C, Sritularak B, Likhitwitayawuid K, Chanvorachote P (2014) Cytotoxic and anti-metastatic activities of phenolic compounds from Dendrobium ellipsophyllum. Anticancer Res 34:6573–6579

    CAS  PubMed  Google Scholar 

  10. Taddei ML, Giannoni E, Fiaschi T, Chiarugi P (2012) Anoikis: an emerging hallmark in health and diseases. J Pathol 226:380–393

    Article  CAS  PubMed  Google Scholar 

  11. Song L, Coppola D, Livingston S, Cress D, Haura EB (2005) Mcl-1 regulates survival and sensitivity to diverse apoptotic stimuli in human non-small cell lung cancer cells. Cancer Biol Ther 4:267–276

    Article  CAS  PubMed  Google Scholar 

  12. Shi Y, Wu H, Zhang M, Ding L, Meng F, Fan X (2013) Expression of the epithelial-mesenchymal transition-related proteins and their clinical significance in lung adenocarcinoma. Diagn Pathol 8:89. doi:10.1186/1746-1596-8-89

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Sever R, Brugge JS (2015) Signal transduction in cancer. Cold Spring Harb Perspect Med. doi:10.1101/cshperspect.a006098

    PubMed  Google Scholar 

  14. Sabbah M, Emami S, Redeuilh G, Julien S, Prévost G, Zimber A, Ouelaa R, Bracke M, De Wever O, Gespach C (2008) Molecular signature and therapeutic perspective of the epithelial-to-mesenchymal transitions in epithelial cancers. Drug Resist Updat 11:123–151

    Article  CAS  PubMed  Google Scholar 

  15. Reddy P, Liu L, Ren C, Lindgren P, Boman K, Shen Y, Lundin E, Ottander U, Rytinki M, Liu K (2005) Formation of E-cadherin-mediated cell-cell adhesion activates AKT and mitogen activated protein kinase via phosphatidylinositol 3 kinase and ligand-independent activation of epidermal growth factor receptor in ovarian cancer cells. Mol Endocrinol 19:2564–2578

    Article  CAS  PubMed  Google Scholar 

  16. Ravid D, Maor S, Werner H, Liscovitch M (2006) Caveolin-1 inhibits anoikis and promotes survival signaling in cancer cells. Adv Enzyme Regul 46:163–175

    Article  CAS  PubMed  Google Scholar 

  17. Powan P, Chanvorachote P (2014) Nitric oxide mediates cell aggregation and mesenchymal to epithelial transition in anoikis-resistant lung cancer cells. Mol Cell Biochem 393:237–245

    Article  CAS  PubMed  Google Scholar 

  18. Peinado H, Olmeda D, Cano A (2007) Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 7:415–428

    Article  CAS  PubMed  Google Scholar 

  19. Paoli P, Giannoni E, Chiarugi P (2013) Anoikis molecular pathways and its role in cancer progression. Biochim Biophys Acta 1833:3481–3498

    Article  CAS  PubMed  Google Scholar 

  20. Pai HC, Chang LH, Peng CY, Chang YL, Chen CC, Shen CC, Teng CM, Pan SL (2013) Moscatilin inhibits migration and metastasis of human breast cancer MDA-MB-231 cells through inhibition of Akt and Twist signaling pathway. J Mol Med (Berl) 91:347–356

    Article  CAS  Google Scholar 

  21. Onder TT, Gupta PB, Mani SA, Yang J, Lander ES, Weinberg RA (2008) Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res 68:3645–3654

    Article  CAS  PubMed  Google Scholar 

  22. Nurwidya F, Takahashi F, Murakami A, Takahashi K (2012) Epithelial mesenchymal transition in drug resistance and metastasis of lung cancer. Cancer Res Treat 44:151–156

    Article  PubMed Central  PubMed  Google Scholar 

  23. Meng F, Wu G (2012) The rejuvenated scenario of epithelial-mesenchymal transition (EMT) and cancer metastasis. Cancer Metastasis Rev 31:455–467

    Article  CAS  PubMed  Google Scholar 

  24. Ma XK, Wang L, Li Y, Yang XM, Zhao P, HaoTang ZhuP, Li L, Chen ZN (2010) HAb18G/CD147 cell-cell contacts confer resistance of a HEK293 subpopulation to anoikis in an E-cadherin-dependent manner. BMC Cell Biol 11:27. doi:10.1186/1471-2121-11-27

    Article  PubMed Central  PubMed  Google Scholar 

  25. Luanpitpong S, Talbott SJ, Rojanasakul Y, Nimmannit U, Pongrakhananon V, Wang L, Chanvorachote P (2010) Regulation of lung cancer cell migration and invasion by reactive oxygen species and caveolin-1. J Biol Chem 285:38832–38840

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Lloyd PG (2012) Caveolin-1, antiapoptosis signaling, and anchorage-independent cell growth. Focus on “Caveolin-1 regulates Mcl-1 stability and anoikis in lung carcinoma cells”. Am J Physiol Cell Physiol 302:C1282–C1283

    Article  CAS  PubMed  Google Scholar 

  27. Li L, Ren CH, Tahir SA, Ren C, Thompson TC (2003) Caveolin-1 maintains activated Akt in prostate cancer cells through scaffolding domain binding site interactions with and inhibition of serine/threonine protein phosphatases PP1 and PP2A. Mol Cell Biol 23:9389–9404

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Larue L, Bellacosa A (2005) Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3′ kinase/AKT pathways. Oncogene 24:7443–7454

    Article  CAS  PubMed  Google Scholar 

  29. Kowitdamrong A, Chanvorachote P, Sritularak B, Pongrakhananon V (2013) Moscatilin inhibits lung cancer cell motility and invasion via suppression of endogenous reactive oxygen species. Biomed Res Int 2013:765894

    Article  PubMed Central  PubMed  Google Scholar 

  30. Klymkowsky MW, Savagner P (2009) Epithelial-mesenchymal transition: a cancer researcher’s conceptual friend and foe. Am J Pathol 174:1588–1593

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Klongkumnuankarn P, Busaranon K, Chanvorachote P, Sritularak B, Jongbunprasert V, Likhitwitayawuid K (2015) Cytotoxic and antimigratory activities of phenolic compounds from Dendrobium brymerianum. Evid Based Complement Alternat Med 2015:350410

    Article  PubMed Central  PubMed  Google Scholar 

  32. Kang HG, Jenabi JM, Zhang J, Keshelava N, Shimada H, May WA, Ng T, Reynolds CP, Triche TJ, Sorensen PH (2007) E-cadherin cell-cell adhesion in ewing tumor cells mediates suppression of anoikis through activation of the ErbB4 tyrosine kinase. Cancer Res 67:3094–3105

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Ho CK, Chen CC (2003) Moscatilin from the orchid Dendrobrium loddigesii is a potential anticancer agent. Cancer Invest 21:729–736

    Article  CAS  PubMed  Google Scholar 

  34. Ho CC, Huang PH, Huang HY, Chen YH, Yang PC, Hsu SM (2002) Up-regulated caveolin-1 accentuates the metastasis capability of lung adenocarcinoma by inducing filopodia formation. Am J Pathol 161:1647–1656

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Guarino M (2007) Epithelial–mesenchymal transition and tumour invasion. Int J Biochem Cell Biol 39:2153–2160

    Article  CAS  PubMed  Google Scholar 

  36. Guadamillas MC, Cerezo A, Del Pozo MA (2011) Overcoming anoikis–pathways to anchorage-independent growth in cancer. J Cell Sci 124:3189–3197

    Article  CAS  PubMed  Google Scholar 

  37. Geiger TR, Peeper DS (2009) Metastasis mechanisms. Biochim Biophys Acta 1796:293–308

    CAS  PubMed  Google Scholar 

  38. Gavert N, Ben-Ze’ev A (2008) Epithelial–mesenchymal transition and the invasive potential of tumors. Trends Mol Med 14:199–209

    Article  CAS  PubMed  Google Scholar 

  39. Floor SL, Dumont JE, Maenhaut C, Raspe E (2012) Hallmarks of cancer: of all cancer cells, all the time? Trends Mol Med 18:509–515

    Article  CAS  PubMed  Google Scholar 

  40. Fenouille N, Tichet M, Dufies M, Pottier A, Mogha A, Soo JK, Rocchi S, Mallavialle A, Galibert MD, Khammari A, Lacour JP, Ballotti R, Deckert M, Tartare-Deckert S (2012) The epithelial-mesenchymal transition (EMT) regulatory factor SLUG (SNAI2) is a downstream target of SPARC and AKT in promoting melanoma cell invasion. PLoS One 7:e40378

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Eccles SA, Welch DR (2007) Metastasis: recent discoveries and novel treatment strategies. Lancet 369:1742–1757

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Chunhacha P, Sriuranpong V, Chanvorachote P (2013) Epithelial-mesenchymal transition mediates anoikis resistance and enhances invasion in pleural effusion-derived human lung cancer cells. Oncol Lett 5:1043–1047

    PubMed Central  CAS  PubMed  Google Scholar 

  43. Chunhacha P, Pongrakhananon V, Rojanasakul Y, Chanvorachote P (2012) Caveolin-1 regulates Mcl-1 stability and anoikis in lung carcinoma cells. Am J Physiol Cell Physiol 302:C1284–C1292

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Chunhacha P, Chanvorachote P (2012) Roles of caveolin-1 on anoikis resistance in non small cell lung cancer. Int J Physiol Pathophysiol Pharmacol 4:149–155

    PubMed Central  CAS  PubMed  Google Scholar 

  45. Chiarugi P, Giannoni E (2008) Anoikis: a necessary death program for anchorage-dependent cells. Biochem Pharmacol 76:1352–1364

    Article  CAS  PubMed  Google Scholar 

  46. Chanvorachote P, Kowitdamrong A, Ruanghirun T, Sritularak B, Mungmee C, Likhitwitayawuid K (2013) Anti-metastatic activities of bibenzyls from Dendrobium pulchellum. Nat Prod Commun 8:115–118

    CAS  PubMed  Google Scholar 

  47. Chanvorachote P, Chunhacha P, Pongrakhananon V (2013) Anoikis: a potential target to prevent lung cancer metastasis? Lung Cancer Manage 2:169–171

    Article  CAS  Google Scholar 

  48. Chaffer CL, Weinberg RA (2011) A perspective on cancer cell metastasis. Science 331:1559–1564

    Article  CAS  PubMed  Google Scholar 

  49. Baum B, Settleman J, Quinlan MP (2008) Transitions between epithelial and mesenchymal states in development and disease. Semin Cell Dev Biol 19:294–308

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This research was funded by the Ratchadapiseksompoch Endowment Fund (2014), Chulalongkorn University (CU-57-003-HR).

Author information

Authors and Affiliations

  1. Faculty of Pharmacy, Rangsit University, Pathum Thani, 12000, Thailand

    Kesarin Busaranon

  2. Cell-Based Drug and Health Product Development Research Unit, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand

    Preeyaporn Plaimee & Pithi Chanvorachote

  3. Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand

    Boonchoo Sritularak

  4. Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand

    Pithi Chanvorachote

Authors
  1. Kesarin Busaranon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Preeyaporn Plaimee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Boonchoo Sritularak
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pithi Chanvorachote
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pithi Chanvorachote.

Ethics declarations

Conflict of interest

All authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Busaranon, K., Plaimee, P., Sritularak, B. et al. Moscatilin inhibits epithelial-to-mesenchymal transition and sensitizes anoikis in human lung cancer H460 cells. J Nat Med 70, 18–27 (2016). https://doi.org/10.1007/s11418-015-0931-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11418-015-0931-7

Keywords

Search

Navigation