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Dendrofalconerol A sensitizes anoikis and inhibits migration in lung cancer cells

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Abstract

Resistance to anoikis, enhanced cell motility, and growth in anchorage-independent conditions are hallmarks of highly metastatic cancer cells. The present study demonstrates the anoikis-sensitizing and anti-migration activities of dendrofalconerol A (DF-A), a pure bis(bibenzyl) isolated from the stem of Dendrobium falconeri (Orchidaceae), and its underlying mechanisms in human lung cancer H460 cells. DF-A at non-toxic concentrations significantly increased the anoikis response of the cancer cells, but caused no toxic effect on normal keratinocytes. In addition, DF-A significantly inhibited the growth of lung cancer cells in anchorage-independent conditions. Western blot analysis revealed that the anoikis-sensitizing effect of such a compound involves its ability to suppress survival signals as well as anti-apoptotic proteins, namely, activated protein kinase B (Akt) and Bcl-2. Furthermore, DF-A decreased caveolin-1 (Cav-1), a protein responsible for aggressiveness, while having no effect on Bax, Mcl-1, and activated Erk (p42/44) proteins. In the case of cell motility, DF-A exhibited strong anti-migration activity with the mechanism involving suppression of pFAK and Rho-GTP, but had no effect on Rac-GTP in lung cancer cells. Taken together, DF-A possesses anoikis-sensitizing activity along with anti-migration effects, and may be developed as a novel active compound for cancer treatment.

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References

  1. Steeg PS, Theodorescu D (2008) Metastasis: a therapeutic target for cancer. Nat Clin Pract Oncol 5:206–219

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Frisch SM, Screaton RA (2001) Anoikis mechanisms. Curr Opin Cell Biol 13:555–562

    Article  CAS  PubMed  Google Scholar 

  3. Wongpankam E, Chunhacha P, Pongrakhananon V, Sritularak B, Chanvorachote P (2012) Artonin E mediates Mcl-1 down-regulation and sensitizes lung cancer cells to anoikis. Anticancer Res 32:5343–5351

    CAS  PubMed  Google Scholar 

  4. Choochuay K, Chunhacha P, Pongrakhananon V, Luechapudiporn R, Chanvorachote P (2013) Imperatorin sensitizes anoikis and inhibits anchorage-independent growth of lung cancer cells. J Nat med 67:599–606

    Article  CAS  PubMed  Google Scholar 

  5. Powan P, Saito N, Suwanborirux K, Chanvorachote P (2013) Ecteinascidin 770, a tetrahydroisoquinoline alkaloid, sensitizes human lung cancer cells to anoikis. Anticancer Res 33:505–512

    CAS  PubMed  Google Scholar 

  6. Pongrakhananon V, Nimmannit U, Luanpitpong S, Rojanasakul Y, Chanvorachote P (2010) Curcumin sensitizes non-small cell lung cancer cell anoikis through reactive oxygen species-mediated Bcl-2 down regulation. Apoptosis 15:574–585

    Article  CAS  PubMed  Google Scholar 

  7. Lin D, Feng J, Chen W (2008) Bcl-2 and caspase-8 related anoikis resistance in human osteosarcoma MG-63 cells. Cell Biol Int 32:1199–1206

    Article  CAS  PubMed  Google Scholar 

  8. Halim H, Chunhacha P, Suwanborirux K, Chanvorachote P (2011) Anticancer and antimetastatic activities of renieramycin M, a marine tetrahydroisoquinoline alkaloid, in human non-small cell lung cancer cells. Anticancer Res 31:193–201

    CAS  PubMed  Google Scholar 

  9. Moon KC, Lee GK, Yoo SH, Jeon YK, Chung JH, Han J, Chung CH (2005) Expression of caveolin-1 in pleomorphic carcinoma of the lung is correlated with a poor prognosis. Anticancer Res 25:4631–4637

    CAS  PubMed  Google Scholar 

  10. Nam KH, Lee BL, Park JH, Kim J, Han N, Lee HE, Kim WH (2013) Caveolin 1 expression correlates with poor prognosis and focal adhesion kinase expression in gastric cancer. Pathobiology 80:87–94

    Article  CAS  PubMed  Google Scholar 

  11. 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 

  12. Rungtabnapa P, Nimmannit U, Halim H, Rojanasakul Y, Chanvorachote P (2011) Hydrogen peroxide inhibits non-small cell lung cancer cell anoikis through the inhibition of caveolin-1 degradation. Am J Physiol 300:C235–C245

    Article  CAS  Google Scholar 

  13. Halim H, Luanpitpong S, Chanvorachote P (2012) Acquisition of anoikis resistance up-regulates caveolin-1 expression in human non-small cell lung cancer cells. Anticancer Res 35:1649–1658

    Google Scholar 

  14. 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 

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

    Article  CAS  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. 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 (Article ID 765894). doi:10.1155/2013/765894

  18. Pongrakhananon V, Chunhacha P, Chanvorachote P (2013) Ouabain suppresses the migratory behavior of lung cancer cells. PLoS One 8:e68623

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Mitra SK, Hanson DA, Schlaepfer DD (2005) Focal adhesion kinase: in command and control of cell motility. Nat Rev Mol Cell Biol 6:56–68

    Article  CAS  PubMed  Google Scholar 

  20. Sieg DJ, Hauck CR, Schlaepfer DD (1999) Required role of focal adhesion kinase (FAK) for integrin-stimulated cell migration. J Cell Sci 112:2677–2691

    CAS  PubMed  Google Scholar 

  21. Sanuphan A, Chunhacha P, Pongrakhananon V, Chanvorachote P, (2013) Long-term nitric oxide exposure enhances lung cancer cell migration. BioMed Res Int 2013 (Article ID 186972). doi:10.1155/2013/186972

  22. Larsen M, Tremblay ML, Yamada KM (2003) Phosphatases in cell-matrix adhesion and migration. Nat Rev Mol Cell Biol 4:700–711

    Article  CAS  PubMed  Google Scholar 

  23. Nobes CD, Hall A (1995) Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell 81:53–62

    Article  CAS  PubMed  Google Scholar 

  24. Sritularak B, Likhitwitayawuid K (2009) New bisbibenzyls from Dendrobium falconeri. Helv Chim Acta 92:740–744

    Article  CAS  Google Scholar 

  25. Wongvaranon P, Pongrakhananon V, Chunhacha P, Chanvorachote P (2013) Acquired resistance to chemotherapy in lung cancer cells mediated by prolonged nitric oxide exposure. Anticancer Res 33:5433–5444

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  27. Rivera E, Gomez H (2010) Chemotherapy resistance in metastatic breast cancer: the evolving role of ixabepilone. Breast Cancer Res 12(suppl 2):S2

    Article  PubMed Central  PubMed  Google Scholar 

  28. Seruga B, Ocana A, Tannock IF (2011) Drug resistance in metastatic castration-resistant prostate cancer. Nat Rev Clin Oncol 8:12–23

    Article  CAS  PubMed  Google Scholar 

  29. Boisvert-Adamo K, Longmate W, Abel EV, Aplin AE (2009) Mcl-1 is required for melanoma cell resistance to anoikis. Mol Cancer Res 7:549–556

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Hakansson A, Gustafsson B, Abdiu A, Krysander L, Hakansson L (2003) Bcl-2 expression in metastatic malignant melanoma. Importance for the therapeutic efficacy of biochemotherapy. Cancer Immunol Immunother 52:249–254

    CAS  PubMed  Google Scholar 

  31. Koshikawa N, Maejima C, Miyazaki K, Nakagawara A, Takenaga K (2006) Hypoxia selects for high-metastatic Lewis lung carcinoma cells overexpressing Mcl-1 and exhibiting reduced apoptotic potential in solid tumors. Oncogene 25:917–928

    Article  CAS  PubMed  Google Scholar 

  32. Kennedy SG, Kandel ES, Cross TK, Hay N (1999) Akt/Protein kinase B inhibits cell death by preventing the release of cytochrome c from mitochondria. Mol Cell Biol 19:5800–5810

    PubMed Central  CAS  PubMed  Google Scholar 

  33. Diaz-Montero CM, Wygant JN, McIntyre BW (2006) PI3-K/Akt-mediated anoikis resistance of human osteosarcoma cells requires Src activation. Eur J Cancer 42:1491–1500

    Article  CAS  PubMed  Google Scholar 

  34. Chanvorachote P, Nimmannit U, Lu Y, Talbott S, Jiang BH, Rojanasakul Y (2009) Nitric oxide regulates lung carcinoma cell anoikis through inhibition of ubiquitin-proteasomal degradation of caveolin-1. J Biol Chem 284:28476–28484

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Serrels B, Serrels A, Brunton VG, Holt M, McLean GW, Gray CH, Jones GE, Frame MC (2007) Focal adhesion kinase controls actin assembly via a FERM mediated interaction with the Arp2/3 complex. Nat Cell Biol 9:1046–1056

    Article  CAS  PubMed  Google Scholar 

  36. Tureckova J, Vojtechova M, Krausova M, Sloncova E, Korinek V (2009) Focal adhesion kinase functions as an akt downstream target in migration of colorectal cancer cells. Transl Oncol 2:281–290

    Article  PubMed Central  PubMed  Google Scholar 

  37. Steffen A, Ladwein M, Dimchev GA, Hein A, Schwenkmezger L, Arens S, Ladwein KI, Margit Holleboom J, Schur F, Victor Small J, Schwarz J, Gerhard R, Faix J, Stradal TE, Brakebusch C, Rottner K (2013) Rac function is crucial for cell migration but is not required for spreading and focal adhesion formation. J Cell Sci 126:4572–4588

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank the 90th anniversary of Chulalongkorn University, Ratchadaphiseksompot Endowment Fund, Chulalongkorn University (CU-57-003-HR), and Mr. Krich Rajprasit, a proofreader.

Conflict of interest

All authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacology and Physiology, Chulalongkorn University, Bangkok, 10330, Thailand

    Premkamol Pengpaeng & Pithi Chanvorachote

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

    Pithi Chanvorachote

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

    Boonchoo Sritularak

  4. Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand

    Premkamol Pengpaeng, Boonchoo Sritularak & Pithi Chanvorachote

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  1. Premkamol Pengpaeng
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  2. Boonchoo Sritularak
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Correspondence to Pithi Chanvorachote.

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Pengpaeng, P., Sritularak, B. & Chanvorachote, P. Dendrofalconerol A sensitizes anoikis and inhibits migration in lung cancer cells. J Nat Med 69, 178–190 (2015). https://doi.org/10.1007/s11418-014-0876-2

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  • DOI: https://doi.org/10.1007/s11418-014-0876-2

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