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EGCG suppresses Fused Toes Homolog protein through p53 in cervical cancer cells

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Abstract

The anticarcinogenic actions of epigallocatechin-3-gallate (EGCG), one of the main ingredients of green tea, against various cancer types including cervical cancer are well documented. Studies pertaining to the exact molecular mechanism by which EGCG induces cancer cell growth inhibition needs to be investigated extensively. In the present study, we observed a stupendous dose dependent reduction in the protein expression of Fused Toes Homolog (FTS) after treatment with EGCG at 1, 10, 25 and 50 μM. Further, we were interested in finding out whether the decrease in the protein expression of FTS was due to decreased mRNA synthesis. Real time reverse transcriptase polymerase chain reaction results revealed a similar dose dependent reduction in the FTS mRNA after EGCG treatment. Chromatin immunoprecipitation analysis revealed the interaction between p53 and the promoter region of FTS. A dose dependent increase in this interaction was evidenced at 25 and 50 μM EGCG treatment. p53 silencing increased the expression of FTS and also decreased the reduction in the levels of FTS expression after EGCG treatment. The decrease in the levels of FTS was more significant at 25 and 50 μM and is associated with reduced physical interaction of FTS with Akt, phosphorylation of Akt and survival of HeLa cells. Collectively, these results conclude that EGCG induced anti-proliferative action in the cervical cancer cell involves reduced mRNA expression of FTS through p53.

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References

  1. Scatchard K, Forrest JL, Flubacher M, Cornes P, Williams C (2012) Chemotherapy for metastatic and recurrent cervical cancer. Cochrane Database Syst Rev 10. doi:10.1002/14651858

  2. Monk BJ, Herzog TJ (2007) The evolution of cost effective screening and prevention of cervical carcinoma: implications of the 2006 consensus guidelines and human papillomavirus vaccination. Am J Obstet Gynecol 197:337–339

    Article  PubMed  Google Scholar 

  3. Cabrera C, Artacho R, Gimenez R (2006) Beneficial effects of green tea—a review. J Am Coll Nutr 25:79–99

    Article  PubMed  CAS  Google Scholar 

  4. Shimizu M, Weinstein IB (2005) Modulation of signal transduction by tea catechins and related phytochemicals. Mutat Res 591:147–160

    Article  PubMed  CAS  Google Scholar 

  5. Shimizu M, Deguchi A, Hara Y et al (2005) EGCG inhibits activation of the insulin-like growth factor-1 receptor in human colon cancer cells. Biochem Biophys Res Commun 334:947–953

    Article  PubMed  CAS  Google Scholar 

  6. Shimizu M, Deguchi A, Joe AK et al (2005) EGCG inhibits activation of HER3 and expression of cyclooxygenase-2 in human colon cancer cells. J Exp Ther Oncol 5:69–78

    PubMed  Google Scholar 

  7. Shimizu M, Deguchi A, Lim JT et al (2005) (-)-Epigallocatechin gallate and polyphenon E inhibit growth and activation of the epidermal growth factor receptor and human epidermal growth factor receptor-2 signaling pathways in human colon cancer cells. Clin Cancer Res 11:2735–2746

    Article  PubMed  CAS  Google Scholar 

  8. Jeong WS, Kim IW, Hu R et al (2004) Modulation of AP-1 by natural chemopreventive compounds in human colon HT-29 cancer cell line. Pharm Res 21:649–660

    Article  PubMed  CAS  Google Scholar 

  9. Hastak K, Agarwal MK, Mukhtar H et al (2005) Ablation of either p21 or Bax prevents p53- dependent apoptosis induced by green tea polyphenol epigallocatechin-3-gallate. FASEB J 19:789–791

    PubMed  CAS  Google Scholar 

  10. Berletch JB, Liu C, Love WK et al (2008) Epigenetic and genetic mechanisms contribute to telomerase inhibition by EGCG. J Cell Biochem 103:509–519

    Article  PubMed  CAS  Google Scholar 

  11. Yang CS, Wang X, Lu G et al (2009) Cancer prevention by tea: animal studies, molecular mechanisms and human relevance. Nat Rev Cancer 9:429–439

    Article  PubMed  CAS  Google Scholar 

  12. Yokoyama M, Noguchi M, Nakao Y et al (2004) The tea polyphenol, (-)epigallocatechin gallate effects on growth apoptosis and telomerase activity in cervical cell lines. Gynecol Oncol 92:197–204

    Article  PubMed  CAS  Google Scholar 

  13. Noguchi M, Yokoyama M, Watanabe S et al (2006) Inhibitory effects of the tea polyphenol (-)epigallocatechin gallate on growth of adenocarcinoma cell lines. Cancer Lett 234:135–142

    Article  PubMed  CAS  Google Scholar 

  14. Lesche R, Peetz A, van der Hoeven F et al (1997) Ft1, a novel gene related to ubiquitin- conjugating enzymes, is deleted in the Fused Toes mouse mutation. Mamm Genome 8:879–883

    Article  PubMed  CAS  Google Scholar 

  15. Peters T, Ausmeier K, Dildrop R et al (2002) The mouse Fused Toes (Ft) mutation is the result of a 1.6-Mb deletion including the entire Iroquois B gene cluster. Mamm Genome 13:186–188

    Article  PubMed  CAS  Google Scholar 

  16. Remy I, Michnick SW (2004) Regulation of apoptosis by the Ft1 protein, a new modulator of protein kinase B/Akt. Mol Cell Biol 24:1493–1504

    Article  PubMed  CAS  Google Scholar 

  17. Xu L, Sowa ME, Chen J et al (2008) An FTS/Hook/p107(FHIP) complex interacts with and promotes endosomal clustering by the homotypic vacuolar protein sorting complex. Mol Biol Cell 19:5059–5071

    Article  PubMed  CAS  Google Scholar 

  18. Cinghu S, Anandharaj A, Lee HC et al (2011) FTS (Fused Toes Homolog) a novel oncoprotein involved in uterine cervical carcinogenesis and a potential diagnostic marker for cervical cancer. J Cell Physiol 226:1564–1572

    Article  PubMed  CAS  Google Scholar 

  19. Muthusami S, Senthilkumar K, Vignesh C et al (2011) Effects of Cissus quadrangularis on the proliferation, differentiation and matrix mineralization of human osteoblast like SaOS-2 cells. J Cell Biochem 112:1035–1045

    Article  PubMed  CAS  Google Scholar 

  20. Qiao Y, Cao J, Xie L, Shi X (2009) Cell growth inhibition and gene expression regulation by (-)- epigallocatechin-3-gallate in human cervical cancer cells. Arch Pharm Res 32:1309–1315

    Article  PubMed  CAS  Google Scholar 

  21. Anandharaj A, Cinghu S, Kim WD et al (2011) Fused Toes Homolog modulates radiation cytotoxicity in uterine cervical cancer cells. Mol Biol Rep 38:5361–5370

    Article  PubMed  CAS  Google Scholar 

  22. Zhang X, Zhang H, Tighiouart M et al (2008) Synergistic inhibition of head and neck tumor growth by green tea (-)-epigallocatechin-3-gallate and EGFR tyrosine kinase inhibitor. Int J Cancer 123:1005–1014

    Article  PubMed  CAS  Google Scholar 

  23. Han DW, Jung DY, Park JC et al (2010) Underlying mechanism for suppression of vascular smooth muscle cells by green tea polyphenol EGCG released from biodegradable polymers for stent application. J Biomed Mater Res A 95:424–433

    PubMed  Google Scholar 

  24. Sah JF, Balasubramanian S, Eckert RL et al (2004) Epigallocatechin-3-gallate inhibits epidermal growth factor receptor signaling pathway. Evidence for direct inhibition of ERK1/2 and AKT kinases. J Biol Chem 279:12755–12762

    Article  PubMed  CAS  Google Scholar 

  25. Thakur VS, Ruhul Amin AR, Paul RK et al (2010) p53-Dependent p21-mediated growth arrest pre-empts and protects HCT116 cells from PUMA-mediated apoptosis induced by EGCG. Cancer Lett 296:225–232

    Article  PubMed  CAS  Google Scholar 

  26. Lee MH, Han DW, Hyon SH et al (2011) Apoptosis of human fibrosarcoma HT-1080cells by epigallocatechin-3-O-gallate via induction of p53 and caspases as well as suppression of Bcl-2 and phosphorylated nuclear factor-κB. Apoptosis 16:75–85

    Article  PubMed  CAS  Google Scholar 

  27. Kang SU, Lee BS, Lee SH et al (2012) Expression of NSAID-activated gene-1 by EGCG in head and neck cancer: involvement of ATM-dependent p53 expression. J Nutr Biochem. doi:10.1016/j.jnutbio.2012.07.003

    Google Scholar 

  28. Lee MH, Na H, Kim EJ et al (2012) Poly(ADP-ribosyl)ation of p53 induces gene specific transcriptional repression of MTA1. Oncogene 31:5099–5107

    Article  PubMed  CAS  Google Scholar 

  29. Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network. Nature 408:307–310

    Article  PubMed  CAS  Google Scholar 

  30. Yu J, Wang Z, Kinzler KW et al (2003) PUMA mediates the apoptotic response of p53 in colorectal cancer cells. Proc Natl Acad Sci USA 100:1931–1936

    Article  PubMed  CAS  Google Scholar 

  31. Yoon CH, Lee ES, Lim DS et al (2009) PKR, a p53 target gene plays a crucial role in the tumor suppressor function of p53. Proc Natl Acad Sci USA 106:7852–7857

    Article  PubMed  CAS  Google Scholar 

  32. Elango R, Alshatwi AA (2013) Naringin induces death receptor and mitochondria mediated apoptosis in human cervical cancer (SiHa) cells. Food Chem Toxicol 51:97–105

    Article  Google Scholar 

  33. Bal DG, Foerster SB, Backman DR et al (2001) Dietary change and cancer: challenges and future direction. J Nutr 131:181–185

    Google Scholar 

  34. Stingl JC, Ettrich T, Muche R et al (2011) Protocol for minimizing the risk of metachronous adenomas of the colorectum with green tea extract (MIRACLE): a randomised controlled trial of green tea extract versus placebo for nutriprevention of metachronous colon adenomas in the elderly population. BMC Cancer 11:360

    Article  PubMed  CAS  Google Scholar 

  35. Wade M, Li YC, Wahl GM (2013) MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer 13:83–96

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This research was supported by the program of Basic Atomic Energy Research Institute (BAERI), which is a part of the Nuclear R & D Programs funded by the Ministry of Education, Science and Technology (MEST) of Korea in 2011.

Conflict of interest

As the corresponding author, I assure that there is no potential conflict of interest exists among the authors regarding financial and personal relationships with other people or organizations that could influence our work.

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Authors and Affiliations

  1. Department of Radiation Oncology, College of Medicine, Chungbuk National University, Cheongju, 361-763, South Korea

    Sridhar Muthusami, D. S. Prabakaran, Zhengzhe An & Woo-Yoon Park

  2. Department of Tropical Medicine and Hygiene, College of Medicine, Konkuk University, Chungju, 380-701, South Korea

    Jae-Ran Yu

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  1. Sridhar Muthusami
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  2. D. S. Prabakaran
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  3. Zhengzhe An
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  4. Jae-Ran Yu
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  5. Woo-Yoon Park
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Correspondence to Woo-Yoon Park.

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Muthusami, S., Prabakaran, D.S., An, Z. et al. EGCG suppresses Fused Toes Homolog protein through p53 in cervical cancer cells. Mol Biol Rep 40, 5587–5596 (2013). https://doi.org/10.1007/s11033-013-2660-x

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  • DOI: https://doi.org/10.1007/s11033-013-2660-x

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