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Article

Luteolin induces intrinsic apoptosis via inhibition of E6/E7 oncogenes and activation of extrinsic and intrinsic signaling pathways in HPV-18-associated cells

  • Authors:
    • Sunyoung Ham
    • Ki Hong Kim
    • Tae Ho Kwon
    • Yesol Bak
    • Dong Hun Lee
    • Yong Seok Song
    • Su-Ho Park
    • Yun Sun Park
    • Man Sub Kim
    • Jeong Woo Kang
    • Jin Tae Hong
    • Do-Young Yoon
  • View Affiliations / Copyright

    Affiliations: Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Republic of Korea, School of Pharmacy, Medical Research Center, Chungbuk National University, Cheongju 361-463, Republic of Korea
  • Pages: 2683-2691
    |
    Published online on: April 25, 2014
       https://doi.org/10.3892/or.2014.3157
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Abstract

Luteolin, a flavonoid extracted from a number of plants with recognized anticancer, anti-inflammatory and anti-oxidative activities, inhibits angiogenic processes and modulates multidrug resistance. However, the efficacy and mechanisms of action of this flavonoid agent are still undergoing study. In order to elucidate whether luteolin exhibits an anticancer effect in cervical cancer cells, HeLa cells were incubated with luteolin and apoptosis was assessed by observing nuclear morphological changes, and performing Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining. Cell cycle analysis, western blotting, RT-PCR and mitochondrial membrane potential measurements were also carried out. Luteolin showed a significant dose-dependent cytotoxic effect only in human papillomavirus (HPV)-positive cervical cancer cells, when compared to its effect on HPV-negative cervical cancer C33A cells. Expression levels of human papilloma virus E6 and E7 oncogenes were suppressed, those of related factors pRb and p53 were recovered and E2F5 was increased by luteolin treatment. Furthermore, luteolin enhanced the expression of death receptors and death receptor downstream factors such as Fas/FasL, DR5/TRAIL and FADD in HeLa cells, and activated caspase cascades. In particular, luteolin enhanced the activity of caspase-3 and -8 in a dose-dependent manner. Activation of caspase-3 induced caspase-8 activity and vice versa. Luteolin also induced mitochondrial membrane potential collapse and cytochrome c release, and inhibited Bcl-2 and Bcl-xL expression. In conclusion, luteolin exerts anticarcinogenic activity through inhibition of E6 and E7 expression and cross-activation of caspase-3 and -8. Taken together, these results suggest that luteolin induces inactivation of HPV-18 oncogene expression and apoptosis by activating the intrinsic and extrinsic pathways.
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1 

Seelinger G, Merfort I, Woelfle U and Schempp CM: Anti-carcinogenic effects of the flavonoid luteolin. Molecules. 13:2628–2651. 2008. View Article : Google Scholar : PubMed/NCBI

2 

Birt DF, Hendrich S and Wang W: Dietary agents in cancer prevention: flavonoids and isoflavonoids. Pharmacol Ther. 90:157–177. 2001. View Article : Google Scholar : PubMed/NCBI

3 

Ren W, Qiao Z, Wang H, Zhu L and Zhang L: Flavonoids: promising anticancer agents. Med Res Rev. 23:519–534. 2003. View Article : Google Scholar

4 

Hoensch H and Oertel R: Anti-inflammatory effects of tea-flavonoids. Dtsch Med Wochenschr. 137:2738–2740. 2012.(In German).

5 

Ju HK, Lee HW, Chung KS, et al: Standardized flavonoid-rich fraction of Artemisia princeps Pampanini cv. Sajabal induces apoptosis via mitochondrial pathway in human cervical cancer HeLa cells. J Ethnopharmacol. 141:460–468. 2012.PubMed/NCBI

6 

Munagala R, Kausar H, Munjal C and Gupta RC: Withaferin A induces p53-dependent apoptosis by repression of HPV oncogenes and upregulation of tumor suppressor proteins in human cervical cancer cells. Carcinogenesis. 32:1697–1705. 2011. View Article : Google Scholar : PubMed/NCBI

7 

Stern PL, van der Burg SH, Hampson IN, et al: Therapy of human papillomavirus-related disease. Vaccine. 30(Suppl 5): F71–F82. 2012. View Article : Google Scholar : PubMed/NCBI

8 

Grabowska AK and Riemer AB: The invisible enemy - how human papillomaviruses avoid recognition and clearance by the host immune system. Open Virol J. 6:249–256. 2012. View Article : Google Scholar : PubMed/NCBI

9 

Teissier S, Pang CL and Thierry F: The E2F5 repressor is an activator of E6/E7 transcription and of the S-phase entry in HPV18-associated cells. Oncogene. 29:5061–5070. 2010. View Article : Google Scholar : PubMed/NCBI

10 

Doorbar J, Quint W, Banks L, et al: The biology and life-cycle of human papillomaviruses. Vaccine. 30(Suppl 5): F55–F70. 2012. View Article : Google Scholar : PubMed/NCBI

11 

Adhim Z, Otsuki N, Kitamoto J, et al: Gene silencing with siRNA targeting E6/E7 as a therapeutic intervention against head and neck cancer-containing HPV16 cell lines. Acta Otolaryngol. 133:761–771. 2013. View Article : Google Scholar : PubMed/NCBI

12 

Jonson AL, Rogers LM, Ramakrishnan S and Downs LS Jr: Gene silencing with siRNA targeting E6/E7 as a therapeutic intervention in a mouse model of cervical cancer. Gynecol Oncol. 111:356–364. 2008. View Article : Google Scholar : PubMed/NCBI

13 

Manzo-Merino J, Thomas M, Fuentes-Gonzalez AM, Lizano M and Banks L: HPV E6 oncoprotein as a potential therapeutic target in HPV related cancers. Expert Opin Ther Targets. 17:1357–1368. 2013. View Article : Google Scholar : PubMed/NCBI

14 

Bosch FX, Broker TR, Forman D, et al: Comprehensive control of human papillomavirus infections and related diseases. Vaccine. 31(Suppl 7): H1–H31. 2013. View Article : Google Scholar

15 

Walker NI, Harmon BV, Gobé GC and Kerr JF: Patterns of cell death. Methods Achiev Exp Pathol. 13:18–54. 1988.

16 

Bak YS, Kim HJ, Kang JW, et al: A synthetic naringenin derivative, 5-hydroxy-7,4′-diacetyloxyflavanone-N-phenyl hydrazone (N101-43), induces apoptosis through up-regulation of Fas/FasL expression and inhibition of PI3K/Akt signaling pathways in non-small-cell lung cancer cells. J Agric Food Chem. 59:10286–10297. 2011.PubMed/NCBI

17 

von Haefen C, Wieder T, Essmann F, Schulze-Osthoff K, Dorken B and Daniel PT: Paclitaxel-induced apoptosis in BJAB cells proceeds via a death receptor-independent, caspases-3/-8-driven mitochondrial amplification loop. Oncogene. 22:2236–2247. 2003.PubMed/NCBI

18 

Chung KS, Choi JH, Back NI, et al: Eupafolin, a flavonoid isolated from Artemisia princeps, induced apoptosis in human cervical adenocarcinoma HeLa cells. Mol Nutr Food Res. 54:1318–1328. 2010.PubMed/NCBI

19 

Franklin JL: Redox regulation of the intrinsic pathway in neuronal apoptosis. Antioxid Redox Signal. 14:1437–1448. 2011. View Article : Google Scholar : PubMed/NCBI

20 

Tan S, de Vries EG, van der Zee AG and de Jong S: Anticancer drugs aimed at E6 and E7 activity in HPV-positive cervical cancer. Curr Cancer Drug Targets. 12:170–184. 2012. View Article : Google Scholar : PubMed/NCBI

21 

Cory AH, Owen TC, Barltrop JA and Cory JG: Use of an aqueous soluble tetrazolium/formazan assay for cell growth assays in culture. Cancer Commun. 3:207–212. 1991.PubMed/NCBI

22 

Daxhelet GA, Coene MM, Hoet PP and Cocito CG: Spectrofluorometry of dyes with DNAs of different base composition and conformation. Anal Biochem. 179:401–403. 1989. View Article : Google Scholar : PubMed/NCBI

23 

Vermes I, Haanen C, Steffens-Nakken H and Reutelingsperger C: A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. J Immunol Methods. 184:39–51. 1995. View Article : Google Scholar

24 

Smiley ST, Reers M, Mottola-Hartshorn C, et al: Intracellular heterogeneity in mitochondrial membrane potentials revealed by a J-aggregate-forming lipophilic cation JC-1. Proc Natl Acad Sci USA. 88:3671–3675. 1991. View Article : Google Scholar : PubMed/NCBI

25 

Milde-Langosch K and Riethdorf S: Role of cell-cycle regulatory proteins in gynecological cancer. J Cell Physiol. 196:224–244. 2003. View Article : Google Scholar : PubMed/NCBI

26 

Yamamoto M, Yoshida M, Ono K, et al: Effect of tumor suppressors on cell cycle-regulatory genes: RB suppresses p34cdc2 expression and normal p53 suppresses cyclin A expression. Exp Cell Res. 210:94–101. 1994. View Article : Google Scholar : PubMed/NCBI

27 

Jin CY, Moon DO, Lee JD, et al: Sulforaphane sensitizes tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis through downregulation of ERK and Akt in lung adenocarcinoma A549 cells. Carcinogenesis. 28:1058–1066. 2007. View Article : Google Scholar

28 

Moody CA and Laimins LA: Human papillomavirus oncoproteins: pathways to transformation. Nat Rev Cancer. 10:550–560. 2010. View Article : Google Scholar : PubMed/NCBI

29 

Bak Y, Ham S, Baatartsogt O, et al: A1E inhibits proliferation and induces apoptosis in NCI-H460 lung cancer cells via extrinsic and intrinsic pathways. Mol Biol Rep. 40:4507–4519. 2013. View Article : Google Scholar : PubMed/NCBI

30 

Doorbar J: Molecular biology of human papillomavirus infection and cervical cancer. Clin Sci. 110:525–541. 2006. View Article : Google Scholar : PubMed/NCBI

31 

Horinaka M, Yoshida T, Shiraishi T, et al: Luteolin induces apoptosis via death receptor 5 upregulation in human malignant tumor cells. Oncogene. 24:7180–7189. 2005. View Article : Google Scholar : PubMed/NCBI

32 

Zhao J, Chen X, Lin W, et al: Total alkaloids of Rubus aleaefolius Poir inhibit hepatocellular carcinoma growth in vivo and in vitro via activation of mitochondrial-dependent apoptosis. Int J Oncol. 42:971–978. 2013.

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Copy and paste a formatted citation
Spandidos Publications style
Ham S, Kim KH, Kwon TH, Bak Y, Lee DH, Song YS, Park S, Park YS, Kim MS, Kang JW, Kang JW, et al: Luteolin induces intrinsic apoptosis via inhibition of E6/E7 oncogenes and activation of extrinsic and intrinsic signaling pathways in HPV-18-associated cells. Oncol Rep 31: 2683-2691, 2014.
APA
Ham, S., Kim, K.H., Kwon, T.H., Bak, Y., Lee, D.H., Song, Y.S. ... Yoon, D. (2014). Luteolin induces intrinsic apoptosis via inhibition of E6/E7 oncogenes and activation of extrinsic and intrinsic signaling pathways in HPV-18-associated cells. Oncology Reports, 31, 2683-2691. https://doi.org/10.3892/or.2014.3157
MLA
Ham, S., Kim, K. H., Kwon, T. H., Bak, Y., Lee, D. H., Song, Y. S., Park, S., Park, Y. S., Kim, M. S., Kang, J. W., Hong, J. T., Yoon, D."Luteolin induces intrinsic apoptosis via inhibition of E6/E7 oncogenes and activation of extrinsic and intrinsic signaling pathways in HPV-18-associated cells". Oncology Reports 31.6 (2014): 2683-2691.
Chicago
Ham, S., Kim, K. H., Kwon, T. H., Bak, Y., Lee, D. H., Song, Y. S., Park, S., Park, Y. S., Kim, M. S., Kang, J. W., Hong, J. T., Yoon, D."Luteolin induces intrinsic apoptosis via inhibition of E6/E7 oncogenes and activation of extrinsic and intrinsic signaling pathways in HPV-18-associated cells". Oncology Reports 31, no. 6 (2014): 2683-2691. https://doi.org/10.3892/or.2014.3157
Copy and paste a formatted citation
x
Spandidos Publications style
Ham S, Kim KH, Kwon TH, Bak Y, Lee DH, Song YS, Park S, Park YS, Kim MS, Kang JW, Kang JW, et al: Luteolin induces intrinsic apoptosis via inhibition of E6/E7 oncogenes and activation of extrinsic and intrinsic signaling pathways in HPV-18-associated cells. Oncol Rep 31: 2683-2691, 2014.
APA
Ham, S., Kim, K.H., Kwon, T.H., Bak, Y., Lee, D.H., Song, Y.S. ... Yoon, D. (2014). Luteolin induces intrinsic apoptosis via inhibition of E6/E7 oncogenes and activation of extrinsic and intrinsic signaling pathways in HPV-18-associated cells. Oncology Reports, 31, 2683-2691. https://doi.org/10.3892/or.2014.3157
MLA
Ham, S., Kim, K. H., Kwon, T. H., Bak, Y., Lee, D. H., Song, Y. S., Park, S., Park, Y. S., Kim, M. S., Kang, J. W., Hong, J. T., Yoon, D."Luteolin induces intrinsic apoptosis via inhibition of E6/E7 oncogenes and activation of extrinsic and intrinsic signaling pathways in HPV-18-associated cells". Oncology Reports 31.6 (2014): 2683-2691.
Chicago
Ham, S., Kim, K. H., Kwon, T. H., Bak, Y., Lee, D. H., Song, Y. S., Park, S., Park, Y. S., Kim, M. S., Kang, J. W., Hong, J. T., Yoon, D."Luteolin induces intrinsic apoptosis via inhibition of E6/E7 oncogenes and activation of extrinsic and intrinsic signaling pathways in HPV-18-associated cells". Oncology Reports 31, no. 6 (2014): 2683-2691. https://doi.org/10.3892/or.2014.3157
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