Advertisement

Tumor Biology

, Volume 37, Issue 7, pp 8633–8641 | Cite as

The attenuation of epithelial to mesenchymal transition and induction of anoikis by gigantol in human lung cancer H460 cells

  • Thitita Unahabhokha
  • Pithi Chanvorachote
  • Varisa Pongrakhananon
Original Article

Abstract

Lung cancer has been the major cause of death within patients due to the high metastatic rate. One of the most essential processes of metastasis is the ability of cancer cells to resist the programmed cell death in a detached condition called anoikis. The discoveries of new natural compound that is able to sensitize anoikis in cancer cells have garnered the most interest in cancer pharmaceutical science. Gigantol, a bibenzyl compound extracted from Dendrobium draconis, has been a promising natural derived compound for cancer therapy due to several cytotoxic effects in cancer cells. This study has demonstrated for the first time that gigantol significantly decreases lung cancer cells’ viability in a detached condition through anoikis and anchorage-independent assays. Western blotting analysis reveals that gigantol greatly decreases epithelial to mesenchymal transition (EMT) markers including N-cadherin, vimentin, and Slug leading to a significant suppression of protein kinase B (AKT), extracellular signal-regulated kinase (ERK), and caveolin-1 (cav-1) survival pathways during the detached condition. Therefore, gigantol could be a potential cancer therapeutic compound suggesting for further development for cancer therapy.

Keywords

Gigantol Anoikis Epithelial to mesenchymal transition Cancer metastasis Lung cancer 

Abbreviations

EMT

Epithelial to mesenchymal transition

AKT

Protein kinase B

ERK

Extracellular signal-regulated kinase

cav-1

Caveolin-1

ECM

Extracellular matrix

Notes

Acknowledgments

The authors would like to thank Professor Boonchoo Sritularak for gigantol preparation. This work was supported by the 100th Anniversary Chulalongkorn University fund for doctoral scholarship and the Ratchadapiseksomphot Endowment Fund (2013), Chulalongkorn University (CU-56-384-HR).

References

  1. 1.
    Chiarugi P, Giannoni E. Anoikis: a necessary death program for anchorage-dependent cells. Biochem Pharmacol. 2008;76(11):1352–64.PubMedCrossRefGoogle Scholar
  2. 2.
    Paoli P, Giannoni E, Chiarugi P. Anoikis molecular pathways and its role in cancer progression. BBA Mol Cell Res. 2013;1833(12):3481–98.Google Scholar
  3. 3.
    Guadamillas MC, Cerezo A, del Pozo MA. Overcoming anoikis—pathways to anchorage-independent growth in cancer. J Cell Sci. 2011;124(19):3189–97.PubMedCrossRefGoogle Scholar
  4. 4.
    Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell. 2004;116:205–19.PubMedCrossRefGoogle Scholar
  5. 5.
    Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH, et al. Classification of cell death: recommendations of the nomenclature committee on cell death 2009. Cell Death Differ. 2008;16(1):3–11.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Yilmaz M, Christofori G. EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev. 2009;28(1–2):15–33.PubMedCrossRefGoogle Scholar
  7. 7.
    Sabbah M, Emami S, Redeuilh G, Julien S, Prévost G, Zimber A, et al. Molecular signature and therapeutic perspective of the epithelial-to-mesenchymal transitions in epithelial cancers. Drug Resist Updat. 2008;11(4–5):123–51.PubMedCrossRefGoogle Scholar
  8. 8.
    Shi Y, Wu H, Zhang M, Ding L, Meng F, Fan X. Expression of the epithelial-mesenchymal transition-related proteins and their clinical significance in lung adenocarcinoma. Diagn Pathol. 2013;8(1):1–1.Google Scholar
  9. 9.
    Geiger TR, Peeper DS. Metastasis mechanisms. BBA Rev Cancer. 2009;1796(2):293–308.Google Scholar
  10. 10.
    Voulgari A, Pintzas A. Epithelial–mesenchymal transition in cancer metastasis: mechanisms, markers and strategies to overcome drug resistance in the clinic. BBA Rev Cancer. 2009;1796(2):75–90.Google Scholar
  11. 11.
    Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119(6):1420–8.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Floor SL, Dumont JE, Maenhaut C, Raspe E. Hallmarks of cancer: of all cancer cells, all the time? Trends Mol Med. 2012;18(9):509–15.PubMedCrossRefGoogle Scholar
  13. 13.
    Powan P, Chanvorachote P. Nitric oxide mediates cell aggregation and mesenchymal to epithelial transition in anoikis-resistant lung cancer cells. Mol Cell Biochem. 2014;393(1–2):237–45.PubMedCrossRefGoogle Scholar
  14. 14.
    Chanvorachote P, Pongrakhananon V, Halim H. Caveolin-1 regulates metastatic behaviors of anoikis resistant lung cancer cells. Mol Cell Biochem. 2014;399(1–2):291–302.PubMedGoogle Scholar
  15. 15.
    Halim H, Luanpitpong S, Chanvorachote P. Acquisition of anoikis resistance up-regulates caveolin-1 expression in human non-small cell lung cancer cells. Anticancer Res. 2012;32(5):1649–58.PubMedGoogle Scholar
  16. 16.
    Ravid D, Maor S, Werner H, Liscovitch M. Caveolin-1 inhibits anoikis and promotes survival signaling in cancer cells. Adv Enzyme Regul. 2006;46(1):163–75.PubMedCrossRefGoogle Scholar
  17. 17.
    Ho C-C, Huang P-H, Huang H-Y, Chen Y-H, Yang P-C, Hsu S-M. Up-regulated caveolin-1 accentuates the metastasis capability of lung adenocarcinoma by inducing filopodia formation. Am J Pathol. 2010;161(5):1647–56.CrossRefGoogle Scholar
  18. 18.
    Chunhacha P, Chanvorachote P. Roles of caveolin-1 on anoikis resistance in non small cell lung cancer. Int J Physiol. 2011;4(3):149–55.Google Scholar
  19. 19.
    Chanvorachote P. Epithelial-mesenchymal transition mediates anoikis resistance and enhances invasion in pleural effusion-derived human lung cancer cells. Oncol Lett. 2013;5:1043–47.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Klongkumnuankarn P, Busaranon K, Chanvorachote P, Sritularak B, Jongbunprasert V, Likhitwitayawuid K. Cytotoxic and antimigratory activities of phenolic compounds from dendrobium brymerianum. J Evid Based Complementary Altern Med. 2015;1–9.Google Scholar
  21. 21.
    Charoenrungruang S, Chanvorachote P, Sritularak B. Gigantol-induced apoptosis in lung cancer cell through mitochondrial-dependent pathway. TJPS. 2014;38:67–73.Google Scholar
  22. 22.
    Charoenrungruang S, Chanvorachote P, Sritularak B, Pongrakhananon V. Gigantol, a bibenzyl from Dendrobium draconis, inhibits the migratory behavior of non-small cell lung cancer cells. J Nat Prod. 2014;77(6):1359–66.PubMedCrossRefGoogle Scholar
  23. 23.
    Sritularak B, Anuwat M, Likhitwitayawuid K. A new phenanthrenequinone from Dendrobium draconis. J Asian Nat Prod Res. 2011;13(3):251–5.PubMedCrossRefGoogle Scholar
  24. 24.
    Bailey KM, Liu J. Caveolin-1 up-regulation during epithelial to mesenchymal transition is mediated by focal adhesion kinase. J Biol Chem. 2008;283(20):13714–24.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Ha G-H, Park J-S, Breuer E-KY. TACC3 promotes epithelial-mesenchymal transition (EMT) through the activation of PI3K/Akt and ERK signaling pathways. Cancer Lett. 2013;332(1):63–73.PubMedCrossRefGoogle Scholar
  26. 26.
    Mehlen P, Puisieux A. Metastasis: a question of life or death. Nat Rev Cancer. 2006;6(6):449–58.PubMedCrossRefGoogle Scholar
  27. 27.
    Weigelt B, Peterse JL, van’t Veer LJ. Breast cancer metastasis: markers and models. Nat Rev Cancer. 2005;5(8):591–602.PubMedCrossRefGoogle Scholar
  28. 28.
    Baum B, Settleman J, Quinlan MP. Transitions between epithelial and mesenchymal states in development and disease. Semin Cell Dev Biol. 2008;19(3):294–308.PubMedCrossRefGoogle Scholar
  29. 29.
    Larue L, Bellacosa A. Epithelial–mesenchymal transition in development and cancer: role of phosphatidylinositol 3′ kinase/AKT pathways. Oncogene. 2005;24(50):7443–54.PubMedCrossRefGoogle Scholar
  30. 30.
    Winitthana T, Lawanprasert S, Chanvorachote P. Triclosan potentiates epithelial-to-mesenchymal transition in anoikis-resistant human lung cancer cells. PLoS ONE. 2014;9(10), e110851.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Thiery JP, Sleeman JP. Complex networks orchestrate epithelial–mesenchymal transitions. Nat Rev Mol Cell Biol. 2006;7(2):131–42.PubMedCrossRefGoogle Scholar
  32. 32.
    Nurwidya F, Takahashi F, Murakami A, Takahashi K. Epithelial mesenchymal transition in drug resistance and metastasis of lung cancer. Cancer Res Treat. 2012;44(3):151–6.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Frisch SM, Schaller M, Cieply B. Mechanisms that link the oncogenic epithelial-mesenchymal transition to suppression of anoikis. J Cell Sci. 2013;126(1):21–9.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Irie HY. Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial-mesenchymal transition. J Cell Biol. 2005;171(6):1023–34.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Enomoto A, Murakami H, Asai N, Morone N, Watanabe T, Kawai K, et al. Akt/PKB regulates actin organization and cell motility via girdin/APE. Dev Cell. 2005;9(3):389–402.PubMedCrossRefGoogle Scholar
  36. 36.
    Song G, Ouyang G, Bao S. The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med. 2005;9(1):59–71.PubMedCrossRefGoogle Scholar
  37. 37.
    Lu Z, Xu S. ERK1/2 MAP kinases in cell survival and apoptosis. IUBMB Life. 2006;58(11):621–31.PubMedCrossRefGoogle Scholar
  38. 38.
    McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EWT, Chang F, et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. BBA Mol Cell Res. 2007;1773(8):1263–84.Google Scholar
  39. 39.
    Zhang W, Liu HT. MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 2012;9–18.Google Scholar
  40. 40.
    Luanpitpong S, Talbott SJ, Rojanasakul Y, Nimmanit U, Pongrakhananon V, Wang L, Chanvorachote P. Regulation of lung cancer cell migration and invasion by reactive oxygen species and caveolin-1. J Biol Chem. 2010;38832–40.Google Scholar
  41. 41.
    Scheel C, Weinberg RA. Cancer stem cells and epithelial–mesenchymal transition: concepts and molecular links. Semin Cancer Biol. 2012;22(5–6):396–403.PubMedCrossRefGoogle Scholar
  42. 42.
    Mani SA, Guo W, Liao M-J, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133(4):704–15.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Vinogradov S, Wei X. Cancer stem cells and drug resistance: the potential of nanomedicine. Nanomedicine. 2012;7(4):597–615.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Lobo NA, Shimono Y, Qian D, Clarke MF. The Biology of Cancer Stem Cells. Annu Rev Cell Dev Biol. 2007;23(1):675–99.PubMedCrossRefGoogle Scholar
  45. 45.
    Yongsanguanchai N, Pongrakhananon V, Mutirangura A, Rojanasakul Y, Chanvorachote P. Nitric oxide induces cancer stem cell-like phenotypes in human lung cancer cells. Am J Physiol. 2015;308(2):89–100.CrossRefGoogle Scholar
  46. 46.
    Chen K, Huang YH, Chen JL. Understanding and targeting cancer stem cells: therapeutic implications and challenges. Nat Commun. 2013;34(6):732–40.Google Scholar
  47. 47.
    Han L, Shi S, Gong T, Zhang Z, Sun X. Cancer stem cells—therapeutic implications and perspectives in cancer therapy. Acta Pharm Sin B. 2013;3(2):65–75.CrossRefGoogle Scholar
  48. 48.
    Jung H-Y, Yang J. Unraveling the TWIST between EMT and cancer stemness. Stem Cells. 2015;16(1):1–2.CrossRefGoogle Scholar
  49. 49.
    Schmidt JM, Panzilius E, Bartsch HS, Irmler M, Beckers J, Kari V, et al. Stem-cell-like properties and epithelial plasticity arise as stable traits after transient twist1 activation. Cell Rep. 2015;10(2):131–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Rajendran G, Dutta D, Hong J, Paul A, Saha B, Mahato B, et al. Inhibition of protein kinase C signaling maintains rat embryonic stem cell pluripotency. J Biol Chem. 2013;288(34):24351–62.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Bhummaphan N, Chanvorachote P. Gigantol suppresses cancer stem cell-like phenotypes in lung cancer cells. J Evid Based Complement Altern Med. 2015;2015(3):1–10.CrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Thitita Unahabhokha
    • 1
    • 3
  • Pithi Chanvorachote
    • 2
    • 3
  • Varisa Pongrakhananon
    • 2
    • 3
  1. 1.Pharmaceutical Technology (International) Program, Faculty of Pharmaceutical SciencesChulalongkorn UniversityBangkokThailand
  2. 2.Department of Pharmacology and Physiology, Faculty of Pharmaceutical SciencesChulalongkorn UniversityBangkokThailand
  3. 3.Cell-Based Drug and Health Product Development Research UnitChulalongkorn UniversityBangkokThailand

Personalised recommendations