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Imperatorin sensitizes anoikis and inhibits anchorage-independent growth of lung cancer cells

Journal of Natural Medicines volume 67, pages 599–606 (2013)Cite this article

Abstract

The anoikis-sensitization activity of imperatorin, an active furanocoumarin component of Angelica dahurica root, is reported herein for the first time. The present study demonstrated that the imperatorin treatment at sub-toxic concentrations enhanced human lung cancer H23 cell apoptosis after detachment. A Western blot analysis showed that imperatorin significantly enhanced the p53 protein level, which subsequently down-regulated Mcl-1 protein and up-regulated Bax, while it had a minimal effect on Bcl-2 expression. In addition, an anchorage-independent growth assay was performed to support the anti-metastasis potential of imperatorin. Consistent with anoikis assay, imperatorin exhibited a strong inhibitory effect on the anchorage-independent growth of the cells. Further, this study demonstrated that imperatorin sensitizes anoikis in other lung cancer cells, namely, H292 and A549. Because anoikis was shown to be a critical hindrance in preventing cancer cell metastasis, the knowledge regarding such an activity and an underlying mechanism may lead to the development of this compound for a cancer therapy.

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References

  1. Kostova I (2005) Synthetic and natural coumarins as cytotoxic agents. Curr Med Chem Anticancer Agents 5:29–46

    PubMed  Article  CAS  Google Scholar 

  2. Baek NI, Ahn EM, Kim HY, Park YD (2000) Furanocoumarins from the root of Angelica dahurica. Arch Pharm Res 23:467–470

    PubMed  Article  CAS  Google Scholar 

  3. Pae HO, Oh H, Yun YG, Oh GS, Jang SI, Hwang KM, Kwon TO, Lee HS, Chung HT (2002) Imperatorin, a furanocoumarin from Angelica dahurica (Umbelliferae), induces cytochrome c-dependent apoptosis in human promyelocytic leukaemia, HL-60 cells. Pharmacol Toxicol 91:40–48

    PubMed  Article  CAS  Google Scholar 

  4. Luo KW, Sun JG, Chan JYW, Yang L, Wu SH, Fung KP, Liu FY (2011) Anticancer effects of imperatorin isolated from Angelica dahurica: induction of apoptosis in HepG2 cells through both death-receptor- and mitochondria-mediated pathways. Chemotherapy 57:449–459

    PubMed  Article  CAS  Google Scholar 

  5. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ (2008) Cancer statistics, 2008. CA Cancer J Clin 58:71–96

    PubMed  Article  Google Scholar 

  6. Herbst RS, Heymach JV, Lippman SM (2008) Lung cancer. N Engl J Med 359:1367–1380

    PubMed  Article  CAS  Google Scholar 

  7. Sun S, Schiller JH, Gazdar AF (2007) Lung cancer in never smokers—a different disease. Nat Rev Cancer 7:778–790

    PubMed  Article  CAS  Google Scholar 

  8. Mountzios G, Fouret P, Soria JC (2008) Mechanisms of disease: signal transduction in lung carcinogenesis—a comparison of smokers and never-smokers. Nat Clin Pract Oncol 5:610–618

    PubMed  Article  CAS  Google Scholar 

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

    PubMed  Article  CAS  Google Scholar 

  10. Christofori G (2003) Changing neighbours, changing behaviour: cell adhesion molecule-mediated signalling during tumour progression. EMBO J 22:2318–2323

    PubMed  Article  CAS  Google Scholar 

  11. Frisch SM (1999) Evidence for a function of death-receptor-related, death-domain-containing proteins in anoikis. Curr Biol 9:1047–1049

    PubMed  Article  CAS  Google Scholar 

  12. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    PubMed  Article  CAS  Google Scholar 

  13. Martin SS, Vuori K (2004) Regulation of Bcl-2 proteins during anoikis and amorphosis. Biochim Biophys Acta 1692:145–157

    PubMed  Article  CAS  Google Scholar 

  14. Galante JM, Mortenson MM, Bowles TL, Virudachalam S, Bold RJ (2009) Erk/Bcl-2 pathway in the resistance of pancreatic cancer to anoikis. J Surg Res 152:18–25

    PubMed  Article  CAS  Google Scholar 

  15. Coultas L, Strasser A (2003) The role of the Bcl-2 protein family in cancer. Semin Cancer Biol 13:115–123

    PubMed  Article  CAS  Google Scholar 

  16. Reginato MJ, Mills KR, Paulus JK, Lynch DK, Sgroi DC, Debnath J, Muthuswamy SK, Brugge JS (2003) Integrins and EGFR coordinately regulate the pro-apoptotic protein Bim to prevent anoikis. Nat Cell Biol 5:733–740

    PubMed  Article  CAS  Google Scholar 

  17. Schmelzle T, Mailleux AA, Overholtzer M, Carroll JS, Solimini NL, Lightcap ES, Veiby OP, Brugge JS (2007) Functional role and oncogene-regulated expression of the BH3-only factor Bmf in mammary epithelial anoikis and morphogenesis. Proc Natl Acad Sci USA 104:3787–3792

    PubMed  Article  CAS  Google Scholar 

  18. Valentijn AJ, Metcalfe AD, Kott J, Streuli CH, Gilmore AP (2003) Spatial and temporal changes in Bax subcellular localization during anoikis. J Cell Biol 162:599–612

    PubMed  Article  CAS  Google Scholar 

  19. Valentijn AJ, Gilmore AP (2004) Translocation of full-length Bid to mitochondria during anoikis. J Biol Chem 279:32848–32857

    PubMed  Article  CAS  Google Scholar 

  20. Frankel A, Rosen K, Filmus J, Kerbel RS (2001) Induction of anoikis and suppression of human ovarian tumor growth in vivo by down-regulation of Bcl-XL. Cancer Res 61:4837–4841

    PubMed  CAS  Google Scholar 

  21. Scorrano L, Korsmeyer SJ (2003) Mechanisms of cytochrome c release by proapoptotic BCL-2 family members. Biochem Biophys Res Commun 304:437–444

    PubMed  Article  CAS  Google Scholar 

  22. Grossmann J, Walther K, Artinger M, Kiessling S, Schölmerich J (2001) Apoptotic signaling during initiation of detachment-induced apoptosis (“anoikis”) of primary human intestinal epithelial cells. Cell Growth Differ 12:147–155

    PubMed  CAS  Google Scholar 

  23. 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

    PubMed  Article  CAS  Google Scholar 

  24. Kim YN, Koo KH, Sung JY, Yun UJ, Kim H (2012) Anoikis resistance: an essential prerequisite for tumor metastasis. Int J Cell Biol 2012:306879

    PubMed  Google Scholar 

  25. Li Z, Zhao J, Du Y, Park HR, Sun Sy, Bernal-Mizrachi L, Aitken A, Khuri FR, Fu H (2008) Down-regulation of 14-3-3ζ suppresses anchorage-independent growth of lung cancer cells through anoikis activation. Proc Natl Acad Sci USA 105:162–167

    PubMed  Article  CAS  Google Scholar 

  26. Woods NT, Yamaguchi H, Lee FY, Bhalla KN, Wang HG (2007) Anoikis, initiated by Mcl-1 degradation and bim induction, is deregulated during oncogenesis. Cancer Res 67:10744–10752

    PubMed  Article  CAS  Google Scholar 

  27. Ramachandra M, Atencio I, Rahman A, Vaillancourt M, Zou A, Avanzini J, Wills K, Bookstein R, Shabram P (2002) Restoration of transforming growth factor β signaling by functional expression of smad4 induces anoikis. Cancer Res 62:6045–6051

    PubMed  CAS  Google Scholar 

  28. Zhu Z, Sanchez-Sweatman O, Huang X, Wiltrout R, Khokha R, Zhao Q, Gorelik E (2000) Anoikis and metastatic potential of cloudman S91 melanoma cells. Cancer Res 61:1707–1716

    Google Scholar 

  29. Koleske AJ, Baltimore D, Lisanti MP (1995) Reduction of caveolin and caveolae in oncogenically transformed cells. Proc Natl Acad Sci USA 92:1381–1385

    PubMed  Article  CAS  Google Scholar 

  30. Cao L, Han L, Zhang Z, Li J, Qu Z, Du J, Liang X, Liu Y, Liu H, Shi Y, Liu S, Gao L, Sun W (2009) Involvement of anoikis-resistance in the metastasis of hepatoma cells. Exp Cell Res 315:1148–1156

    PubMed  Article  CAS  Google Scholar 

  31. Kodama K, Ishii G, Miyamoto S, Goya M, Zhang SC, Sangai T, Yoshikawa T, Hasebe T, Hitomi Y, Izumi K, Ochiai A (2005) Laminin 5 expression protects against anoikis at aerogenous spread and lepidic growth of human lung adenocarcinoma. Int J Cancer 116:876–884

    PubMed  Article  CAS  Google Scholar 

  32. Wei L, Yang Y, Zhang X, Yu Q (2002) Anchorage-independent phosphorylation of p130(Cas) protects lung adenocarcinoma cells from anoikis. J Cell Biochem 87:439–449

    PubMed  Article  CAS  Google Scholar 

  33. Kroemer G, Galluzzi L, Brenner C (2007) Mitochondrial membrane permeabilization in cell death. Physiol Rev 87:99–163

    PubMed  Article  CAS  Google Scholar 

  34. Zuo J, Ishikawa T, Boutros S, Xiao Z, Humtsoe JO, Kramer RH (2010) Bcl-2 overexpression induces a partial epithelial to mesenchymal transition and promotes squamous carcinoma cell invasion and metastasis. Mol Cancer Res 8:170–182

    PubMed  Article  CAS  Google Scholar 

  35. Yang TM, Barbone D, Fennell DA, Broaddus VC (2009) Bcl-2 family proteins contribute to apoptotic resistance in lung cancer multicellular spheroids. Am J Respir Cell Mol Biol 41:14–23

    PubMed  Article  CAS  Google Scholar 

  36. Song L, Coppola D, Livingston S, Cress WD, 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

    PubMed  Article  CAS  Google Scholar 

  37. 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

    PubMed  Article  CAS  Google Scholar 

  38. Schuler M, Green DR (2001) Mechanisms of p53-dependent apoptosis. Biochem Soc Trans 29:684–688

    PubMed  Article  CAS  Google Scholar 

  39. Benchimol S (2001) p53-dependent pathways of apoptosis. Cell Death Differ 8:1049–1051

    PubMed  Article  CAS  Google Scholar 

  40. Ravid D, Maor S, Werner H, Liscovitch M (2005) Caveolin-1 inhibits cell detachment-induced p53 activation and anoikis by upregulation of insulin-like growth factor-I receptors and signaling. Oncogene 24:1338–1347

    PubMed  Article  CAS  Google Scholar 

  41. Song W, Wang J, Yang Y, Jing N, Zhang X, Chen L, Wu J (2012) Rewiring drug-activated p53-regulatory network from suppressing to promoting tumorigenesis. J Mol Cell Biol 4:197–206

    PubMed  Article  CAS  Google Scholar 

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

    PubMed  Article  CAS  Google Scholar 

  43. Derouet M, Wu X, May L, Yoo BH, Sasazuki T, Shirasawa S, Rak J, Rosen KV (2007) Acquisition of anoikis resistance promotes the emergence of oncogenic K-ras mutations in colorectal cancer cells and stimulates their tumorigenicity in vivo. Neoplasia 9:536–545

    PubMed  Article  CAS  Google Scholar 

  44. Grossmann J (2002) Molecular mechanisms of “detachment-induced apoptosis—Anoikis”. Apoptosis 7:247–260

    PubMed  Article  CAS  Google Scholar 

  45. Zhang Y, Lu H, Dazin P, Kapila Y (2004) Squamous cell carcinoma cell aggregates escape suspension-induced, p53-mediated anoikis: fibronectin and integrin alphav mediate survival signals through focal adhesion kinase. J Biol Chem 279:48342–48349

    PubMed  Article  CAS  Google Scholar 

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Acknowledgments

This research was supported by the Thailand Research Fund (to P. Chanvorachote) and the 90th Anniversary of Chulalongkorn University Fund (Ratchadaphiseksomphot Endowment Fund). The authors wish to thank Mr. Krich Rajprasit (Srinakharinwirot University) for proofreading the manuscript.

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

    Kanuengnit Choochuay, Preedakorn Chunhacha, Varisa Pongrakhananon, Rataya Luechapudiporn & Pithi Chanvorachote

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  1. Kanuengnit Choochuay
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  2. Preedakorn Chunhacha
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  3. Varisa Pongrakhananon
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  4. Rataya Luechapudiporn
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  5. Pithi Chanvorachote
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Correspondence to Rataya Luechapudiporn or Pithi Chanvorachote.

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Choochuay, K., Chunhacha, P., Pongrakhananon, V. et al. Imperatorin sensitizes anoikis and inhibits anchorage-independent growth of lung cancer cells. J Nat Med 67, 599–606 (2013). https://doi.org/10.1007/s11418-012-0719-y

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  • DOI: https://doi.org/10.1007/s11418-012-0719-y

Keywords

  • Imperatorin
  • Anoikis
  • Anchorage-independent growth
  • Lung cancer cells