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Flavone initiates a hierarchical activation of the caspase-cascade in colon cancer cells

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Abstract

There is emerging evidence that dietary factors can prevent cancer by affecting the process of carcinogenesis. Flavonoids present in vegeterian food possess antioxidant activities, have scavenging effects on activated carcinogens and mutagens, affect cell cycle progression and alter gene and protein expression. We report here that flavone, the core structure of the flavone subgroup, potently inhibits proliferation and induces apoptosis in HCT-116 colon cancer cells. Flavone induces the activation of caspases 2, 3, 8, 9 and 10 and a decrease of mitochondrial anti-apoptotic Bcl2 protein expression. Further analysis revealed that caspase 10 activation is mediated via caspase 1. Additionally, treatment with flavone results in release of the mitochondrial apoptosis-inducing factor (AIF), the key trigger of caspase-independent apoptosis, into the cytosol. In summary, our data show that flavone induces apoptosis in a caspase-dependent and -independent manner.

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References

  1. Stein CJ, Colditz GA. Modifiable risk factors for cancer. Br J Cancer 2004; 90: 299–303.

    Article  CAS  PubMed  Google Scholar 

  2. Potter JD. Risk factors for colon neoplasia—epidemiology and biology. Eur J Cancer 1995; 31A: 1033–1038.

    Article  CAS  PubMed  Google Scholar 

  3. Slattery ML, Potter JD, Friedman GD, Ma KN, Edwards S. Tobacco use and colon cancer. Int J Cancer 1997; 70: 259–264.

    Article  CAS  PubMed  Google Scholar 

  4. Slattery ML, Boucher KM, Caan BJ, Potter JD, Ma KN. Eating patterns and risk of colon cancer. Am J Epidemiol 1998; 148: 4–16.

    CAS  PubMed  Google Scholar 

  5. Potter JD, Slattery ML, Bostick RM, Gapstur SM. Colon cancer: A review of the epidemiology. Epidemiol Rev 1993; 15: 499–545.

    CAS  PubMed  Google Scholar 

  6. Steinmetz KA, Kushi LH, Bostick RM, Folsom AR, Potter JD. Vegetables, fruit, and colon cancer in the Iowa Women’s Health Study. Am J Epidemiol 1994; 139: 1–15.

    PubMed  Google Scholar 

  7. Johnson IT. New approaches to the role of diet in the prevention of cancers of the alimentary tract. Mutat Res 2004; 551: 9–28.

    CAS  PubMed  Google Scholar 

  8. Witte JS, Longnecker MP, Bird CL, et al. Relation of vegetable, fruit, and grain consumption to colorectal adenomatous polyps. Am J Epidemiol 1996; 144: 1015–1025.

    CAS  PubMed  Google Scholar 

  9. Knekt P, Jarvinen R, Seppanen R, et al. Dietary flavonoids and the risk of lung cancer and other malignant neoplasms. Am J Epidemiol 1997; 146: 223–230.

    CAS  PubMed  Google Scholar 

  10. Peterson J, Dwyer J. Taxonomic classification helps identify flavonoid-containing foods on a semiquantitative food frequency questionnaire. J Am Diet Assoc 1998; 98: 677–682, 685; quiz 683–684.

    Article  CAS  PubMed  Google Scholar 

  11. Duthie SJ, Dobson VL. Dietary flavonoids protect human colonocyte DNA from oxidative attack in vitro. Eur J Nutr 1999; 38: 28–34.

    Article  CAS  PubMed  Google Scholar 

  12. Williamson G, Faulkner K, Plumb GW. Glucosinolates and phenolics as antioxidants from plant foods. Eur J Cancer Prev 1998; 7: 17–21.

    CAS  PubMed  Google Scholar 

  13. Calomme M, Pieters L, Vlietinck A, Vanden Berghe D. Inhibition of bacterial mutagenesis by Citrus flavonoids. Planta Med 1996; 62: 222–226.

    CAS  PubMed  Google Scholar 

  14. Plaumann B, Fritsche M, Rimpler H, Brandner G, Hess RD. Flavonoids activate wild-type p53. Oncogene 1996; 13: 1605–1614.

    CAS  PubMed  Google Scholar 

  15. Gerritsen ME. Flavonoids: Inhibitors of cytokine induced gene expression. Adv Exp Med Biol 1998; 439: 183–190.

    CAS  PubMed  Google Scholar 

  16. Cova D, De Angelis L, Giavarini F, Palladini G, Perego R. Pharmacokinetics and metabolism of oral diosmin in healthy volunteers. Int J Clin Pharmacol Ther Toxicol 1992; 30: 29– 33.

    CAS  PubMed  Google Scholar 

  17. Xu X, Wang HJ, Murphy PA, Cook L, Hendrich S. Daidzein is a more bioavailable soymilk isoflavone than is genistein in adult women. J Nutr 1994; 124: 825–832.

    CAS  PubMed  Google Scholar 

  18. King RA, Bursill DB. Plasma and urinary kinetics of the isoflavones daidzein and genistein after a single soy meal in humans. Am J Clin Nutr 1998; 67: 867–872.

    CAS  PubMed  Google Scholar 

  19. Hollman PC, de Vries JH, van Leeuwen SD, Mengelers MJ, Katan MB. Absorption of dietary quercetin glycosides and quercetin in healthy ileostomy volunteers. Am J Clin Nutr 1995; 62: 1276–1282.

    CAS  PubMed  Google Scholar 

  20. Kuo SM. Transepithelial transport and accumulation of flavone in human intestinal Caco-2 cells. Life Sci 1998; 63: 2323–2331.

    Article  CAS  PubMed  Google Scholar 

  21. Wenzel U, Kuntz S, Brendel MD, Daniel H. Dietary flavone is a potent apoptosis inducer in human colon carcinoma cells. Cancer Res 2000; 60: 3823–3831.

    CAS  PubMed  Google Scholar 

  22. Herzog A, Kindermann B, Doring F, Daniel H, Wenzel U. Pleiotropic molecular effects of the pro-apoptotic dietary constituent flavone in human colon cancer cells identified by protein and mRNA expression profiling. Proteomics 2004; 4: 2455–2464.

    Article  CAS  PubMed  Google Scholar 

  23. Scaffidi C, Fulda S, Srinivasan A, et al. Two CD95 (APO-1/Fas) signaling pathways. Embo J 1998; 17: 1675–1687.

    CAS  PubMed  Google Scholar 

  24. Ozoren N, El-Deiry WS. Defining characteristics of Types I and II apoptotic cells in response to TRAIL. Neoplasia 2002; 4: 551–557.

    PubMed  Google Scholar 

  25. Lin CF, Chen CL, Chang WT, et al. Sequential caspase-2 and caspase-8 activation upstream of mitochondria during ceramideand etoposide-induced apoptosis. J Biol Chem 2004; 279: 40755–40761. Epub 2004 Jul 15.

    Article  CAS  PubMed  Google Scholar 

  26. Hirata H, Takahashi A, Kobayashi S, et al. Caspases are activated in a branched protease cascade and control distinct downstream processes in Fas-induced apoptosis. J Exp Med 1998; 187: 587–600.

    Article  CAS  PubMed  Google Scholar 

  27. Talanian RV, Quinlan C, Trautz S, et al. Substrate specificities of caspase family proteases. J Biol Chem 1997; 272: 9677–9682.

    Article  CAS  PubMed  Google Scholar 

  28. Daugas E, Susin SA, Zamzami N, et al. Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis. Faseb J 2000; 14: 729–739.

    CAS  PubMed  Google Scholar 

  29. Susin SA, Lorenzo HK, Zamzami N, et al. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 1999; 397: 441–446.

    Article  CAS  PubMed  Google Scholar 

  30. Slee EA, Harte MT, Kluck RM, et al. Ordering the cytochrome c-initiated caspase cascade: Hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner. J Cell Biol 1999; 144: 281–292.

    CAS  PubMed  Google Scholar 

  31. Lassus P, Opitz-Araya X, Lazebnik Y. Requirement for caspase-2 in stress-induced apoptosis before mitochondrial permeabilization. Science 2002; 297: 1352–1354.

    CAS  PubMed  Google Scholar 

  32. Guo Y, Srinivasula SM, Druilhe A, Fernandes-Alnemri T, Alnemri ES. Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria. J Biol Chem 2002; 277: 13430–13437. Epub 2002 Feb 06.

    CAS  PubMed  Google Scholar 

  33. Robertson JD, Enoksson M, Suomela M, Zhivotovsky B, Orrenius S. Caspase-2 acts upstream of mitochondria to promote cytochrome c release during etoposide-induced apoptosis. J Biol Chem 2002; 277: 29803–29809.

    Article  CAS  PubMed  Google Scholar 

  34. Wagner KW, Engels IH, Deveraux QL. Caspase-2 can function upstream of bid cleavage in the TRAIL apoptosis pathway. J Biol Chem 2004; 279: 35047–35052. Epub 2004 Jun 01.

    Article  CAS  PubMed  Google Scholar 

  35. Enoksson M, Robertson JD, Gogvadze V, et al. Caspase-2 permeabilizes the outer mitochondrial membrane and disrupts the binding of cytochrome c to anionic phospholipids. J Biol Chem 2004; 8: 8.

    Google Scholar 

  36. Susin SA, Lorenzo HK, Zamzami N, et al. Mitochondrial release of caspase-2 and -9 during the apoptotic process. J Exp Med 1999; 189: 381–394.

    CAS  PubMed  Google Scholar 

  37. Baliga BC, Read SH, Kumar S. The biochemical mechanism of caspase-2 activation. Cell Death Differ 2004; 11: 1234–1241.

    Article  CAS  PubMed  Google Scholar 

  38. Chen M, Wang J. Initiator caspases in apoptosis signaling pathways. Apoptosis 2002; 7: 313–319.

    CAS  PubMed  Google Scholar 

  39. Creagh EM, Conroy H, Martin SJ. Caspase-activation pathways in apoptosis and immunity. Immunol Rev 2003; 193: 10–21.

    Article  CAS  PubMed  Google Scholar 

  40. Martinon F, Tschopp J. Inflammatory caspases: Linking an intracellular innate immune system to autoinflammatory diseases. Cell 2004; 117: 561–574.

    Article  CAS  PubMed  Google Scholar 

  41. Sergeev IN. Genistein induces Ca2+ -mediated, calpain/caspase-12-dependent apoptosis in breast cancer cells. Biochem Biophys Res Commun 2004; 321: 462–467.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to R. Göke MD.

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Erhart, L.M., Lankat-Buttgereit, B., Schmidt, H. et al. Flavone initiates a hierarchical activation of the caspase-cascade in colon cancer cells. Apoptosis 10, 611–617 (2005). https://doi.org/10.1007/s10495-005-1895-y

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  • DOI: https://doi.org/10.1007/s10495-005-1895-y

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