Epigallocatechin gallate promotes p53 accumulation and activity via the inhibition of MDM2-mediated p53 ubiquitination in human lung cancer cells

Jin,Longyu; Li,Cui; Xu,Yan; Wang,Li; Liu,Jianxin; Wang,Dianjun; Hong,Cao; Jiang,Zhibing; Ma,Yuchao; Chen,Qian; Yu,Fenglei

doi:10.3892/or.2013.2343

Epigallocatechin gallate promotes p53 accumulation and activity via the inhibition of MDM2-mediated p53 ubiquitination in human lung cancer cells

Authors:
- Longyu Jin
- Cui Li
- Yan Xu
- Li Wang
- Jianxin Liu
- Dianjun Wang
- Cao Hong
- Zhibing Jiang
- Yuchao Ma
- Qian Chen
- Fenglei Yu
View Affiliations

Affiliations: Cardiothoracic Surgery, The Third XiangYa Hospital, Central South University, Changsha, Hunan 410013, P.R. China, Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China, Cancer Research Institute, XiangYa Medical School, Central South University, Changsha, Hunan 410078, P.R. China, Cardiothoracic Surgery, The Second XiangYa Hospital, Central South University, Changsha, Hunan 410011, P.R. China
Published online on: March 12, 2013 https://doi.org/10.3892/or.2013.2343
Pages: 1983-1990

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Epigallocatechin gallate (EGCG), which is derived from green tea, is well known for its chemopreventive activity. Several studies have shown that p53 plays an important role in the activity of EGCG; however, the mechanism by which EGCG regulates p53 requires further investigation. In the present study, we showed that EGCG inhibits anchorage-independent growth of human lung cancer cells by upregulating p53 expression. EGCG treatment can substantially increase p53 stability, promote nuclear localization of p53 and decrease nuclear accumulation of MDM2. We also found that EGCG increases the phosphorylation of p53 at Ser15 and Ser20 and enhances its transcriptional activity. Although EGCG promotes MDM2 expression in a p53-dependent manner, the interaction between MDM2 and p53 was significantly inhibited following EGCG treatment, which resulted in the inhibition of MDM2-mediated p53 ubiquitination. Thus, our results suggest that the stabilization and activation of p53 may partly contribute to the anticancer activity of EGCG.

View Figures

View References

1	Chen L and Zhang HY: Cancer preventive mechanisms of the green tea polyphenol (−)-epigallocatechin-3-gallate. Molecules. 12:946–957. 2007.
2	Johnson R, Bryant S and Huntley AL: Green tea and green tea catechin extracts: an overview of the clinical evidence. Maturitas. 73:280–287. 2012. View Article : Google Scholar : PubMed/NCBI
3	Fujiki H and Suganuma M: Green tea: an effective synergist with anticancer drugs for tertiary cancer prevention. Cancer Lett. 324:119–125. 2012. View Article : Google Scholar : PubMed/NCBI
4	Fujiki H, Imai K, Nakachi K, Shimizu M, Moriwaki H and Suganuma M: Challenging the effectiveness of green tea in primary and tertiary cancer prevention. J Cancer Res Clin Oncol. 138:1259–1270. 2012. View Article : Google Scholar : PubMed/NCBI
5	Surh YJ: Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer. 3:768–780. 2003. View Article : Google Scholar : PubMed/NCBI
6	Yang CS and Wang X: Green tea and cancer prevention. Nutr Cancer. 62:931–937. 2010. View Article : Google Scholar : PubMed/NCBI
7	Singh BN, Shankar S and Srivastava RK: Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications. Biochem Pharmacol. 82:1807–1821. 2011. View Article : Google Scholar : PubMed/NCBI
8	Khan N, Afaq F, Saleem M, Ahmad N and Mukhtar H: Targeting multiple signaling pathways by green tea polyphenol (−)-epigallocatechin-3-gallate. Cancer Res. 66:2500–2505. 2006.
9	Shimizu M, Deguchi A, Lim JT, Moriwaki H, Kopelovich L and Weinstein IB: (−)-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. 2005.
10	Yang CS, Wang H, Li GX, Yang Z, Guan F and Jin H: Cancer prevention by tea: evidence from laboratory studies. Pharmacol Res. 64:113–122. 2011. View Article : Google Scholar : PubMed/NCBI
11	Levites Y, Amit T, Youdim MB and Mandel S: Involvement of protein kinase C activation and cell survival/cell cycle genes in green tea polyphenol (−)-epigallocatechin 3-gallate neuroprotective action. J Biol Chem. 277:30574–30580. 2002.PubMed/NCBI
12	Relat J, Blancafort A, Oliveras G, Cufi S, Haro D, Marrero PF and Puig T: Different fatty acid metabolism effects of (−)-epigallocatechin-3-gallate and C75 in adenocarcinoma lung cancer. BMC Cancer. 12:2802012.
13	Sah JF, Balasubramanian S, Eckert RL and Rorke EA: 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. 2004. View Article : Google Scholar : PubMed/NCBI
14	Kanwar J, Taskeen M, Mohammad I, Huo C, Chan TH and Dou QP: Recent advances on tea polyphenols. Front Biosci (Elite Ed). 4:111–131. 2012. View Article : Google Scholar : PubMed/NCBI
15	Pianetti S, Guo S, Kavanagh KT and Sonenshein GE: Green tea polyphenol epigallocatechin-3 gallate inhibits Her-2/neu signaling, proliferation, and transformed phenotype of breast cancer cells. Cancer Res. 62:652–655. 2002.PubMed/NCBI
16	Yang F, Oz HS, Barve S, de Villiers WJ, McClain CJ and Varilek GW: The green tea polyphenol (−)-epigallocatechin-3-gallate blocks nuclear factor-kappa B activation by inhibiting I kappa B kinase activity in the intestinal epithelial cell line IEC-6. Mol Pharmacol. 60:528–533. 2001.
17	Ahmad N, Feyes DK, Nieminen AL, Agarwal R and Mukhtar H: Green tea constituent epigallocatechin-3-gallate and induction of apoptosis and cell cycle arrest in human carcinoma cells. J Natl Cancer Inst. 89:1881–1886. 1997. View Article : Google Scholar : PubMed/NCBI
18	Saha A, Kuzuhara T, Echigo N, Suganuma M and Fujiki H: New role of (−)-epicatechin in enhancing the induction of growth inhibition and apoptosis in human lung cancer cells by curcumin. Cancer Prev Res. 3:953–962. 2010.
19	Chang CM, Chang PY, Tu MG, et al: Epigallocatechin gallate sensitizes CAL-27 human oral squamous cell carcinoma cells to the anti-metastatic effects of gefitinib (Iressa) via synergistic suppression of epidermal growth factor receptor and matrix metalloproteinase-2. Oncol Rep. 28:1799–1807. 2012.
20	Deng YT and Lin JK: EGCG inhibits the invasion of highly invasive CL1-5 lung cancer cells through suppressing MMP-2 expression via JNK signaling and induces G2/M arrest. J Agric Food Chem. 59:13318–13327. 2011. View Article : Google Scholar : PubMed/NCBI
21	Jung YD and Ellis LM: Inhibition of tumour invasion and angiogenesis by epigallocatechin gallate (EGCG), a major component of green tea. Int J Exp Pathol. 82:309–316. 2001. View Article : Google Scholar : PubMed/NCBI
22	Liu LC, Tsao TC, Hsu SR, Wang HC, Tsai TC, Kao J and Way TD: EGCG inhibits transforming growth factor-β-mediated epithelial-to-mesenchymal transition via the inhibition of Smad2 and Erk1/2 signaling pathways in nonsmall cell lung cancer cells. J Agric Food Chem. 60:9863–9873. 2012.
23	Singh T and Katiyar SK: Green tea catechins reduce invasive potential of human melanoma cells by targeting COX-2, PGE2 receptors and epithelial-to-mesenchymal transition. PLoS One. 6:e252242011. View Article : Google Scholar
24	Watanabe T, Kuramochi H, Takahashi A, et al: Higher cell stiffness indicating lower metastatic potential in B16 melanoma cell variants and in (−)-epigallocatechin gallate-treated cells. J Cancer Res Clin Oncol. Feb 2–2012.(Epub ahead of print).
25	Charvet C, Wissler M, Brauns-Schubert P, et al: Phosphorylation of Tip60 by GSK-3 determines the induction of PUMA and apoptosis by p53. Mol Cell. 42:584–596. 2011. View Article : Google Scholar : PubMed/NCBI
26	Dai C, Tang Y, Jung SY, Qin J, Aaronson SA and Gu W: Differential effects on p53-mediated cell cycle arrest vs. apoptosis by p90. Proc Natl Acad Sci USA. 108:18937–18942. 2011. View Article : Google Scholar : PubMed/NCBI
27	Dai C and Gu W: p53 post-translational modification: deregulated in tumorigenesis. Trends Mol Med. 16:528–536. 2010. View Article : Google Scholar : PubMed/NCBI
28	Kruse JP and Gu W: SnapShot: p53 post-translational modifications. Cell. 133:930–930.e1. 2008. View Article : Google Scholar
29	Kruse JP and Gu W: Modes of p53 regulation. Cell. 137:609–622. 2009. View Article : Google Scholar
30	Munoz-Fontela C, Gonzalez D, Marcos-Villar L, et al: Acetylation is indispensable for p53 antiviral activity. Cell Cycle. 10:3701–3705. 2011. View Article : Google Scholar : PubMed/NCBI
31	Sakaguchi K, Herrera JE, Saito S, et al: DNA damage activates p53 through a phosphorylation-acetylation cascade. Genes Dev. 12:2831–2841. 1998. View Article : Google Scholar : PubMed/NCBI
32	Jimenez GS, Khan SH, Stommel JM and Wahl GM: p53 regulation by post-translational modification and nuclear retention in response to diverse stresses. Oncogene. 18:7656–7665. 1999. View Article : Google Scholar : PubMed/NCBI
33	Lee JT and Gu W: The multiple levels of regulation by p53 ubiquitination. Cell Death Differ. 17:86–92. 2010. View Article : Google Scholar : PubMed/NCBI
34	Yuan J, Luo K, Zhang L, Cheville JC and Lou Z: USP10 regulates p53 localization and stability by deubiquitinating p53. Cell. 140:384–396. 2010. View Article : Google Scholar : PubMed/NCBI
35	Amin AR, Wang D, Zhang H, et al: Enhanced anti-tumor activity by the combination of the natural compounds (−)-epigallocatechin-3-gallate and luteolin: potential role of p53. J Biol Chem. 285:34557–34565. 2010.
36	Hastak K, Gupta S, Ahmad N, Agarwal MK, Agarwal ML and Mukhtar H: Role of p53 and NF-kappaB in epigallocatechin-3-gallate-induced apoptosis of LNCaP cells. Oncogene. 22:4851–4859. 2003. View Article : Google Scholar : PubMed/NCBI
37	Lee MH, Han DW, Hyon SH and Park JC: Apoptosis of human fibrosarcoma HT-1080 cells by epigallocatechin-3-O-gallate via induction of p53 and caspases as well as suppression of Bcl-2 and phosphorylated nuclear factor-kappaB. Apoptosis. 16:75–85. 2011. View Article : Google Scholar : PubMed/NCBI
38	Qin J, Chen HG, Yan Q, et al: Protein phosphatase-2A is a target of epigallocatechin-3-gallate and modulates p53-Bak apoptotic pathway. Cancer Res. 68:4150–4162. 2008. View Article : Google Scholar : PubMed/NCBI
39	Hastak K, Agarwal MK, Mukhtar H and Agarwal ML: Ablation of either p21 or Bax prevents p53-dependent apoptosis induced by green tea polyphenol epigallocatechin-3-gallate. FASEB J. 19:789–791. 2005.PubMed/NCBI
40	Thakur VS, Ruhul Amin AR, Paul RK, et al: p53-Dependent p21-mediated growth arrest pre-empts and protects HCT116 cells from PUMA-mediated apoptosis induced by EGCG. Cancer Lett. 296:225–232. 2010. View Article : Google Scholar : PubMed/NCBI
41	Zhao BX, Chen HZ, Lei NZ, et al: p53 mediates the negative regulation of MDM2 by orphan receptor TR3. EMBO J. 25:5703–5715. 2006. View Article : Google Scholar : PubMed/NCBI
42	Chehab NH, Malikzay A, Stavridi ES and Halazonetis TD: Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage. Proc Natl Acad Sci USA. 96:13777–13782. 1999. View Article : Google Scholar : PubMed/NCBI
43	Unger T, Juven-Gershon T, Moallem E, et al: Critical role for Ser20 of human p53 in the negative regulation of p53 by Mdm2. EMBO J. 18:1805–1814. 1999. View Article : Google Scholar : PubMed/NCBI