Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Role of p53 and NF-κB in epigallocatechin-3-gallate-induced apoptosis of LNCaP cells

Abstract

We have recently shown that oral consumption of green tea polyphenols inhibits prostate carcinogenesis in transgenic mouse model of prostate cancer and suggested that induction of apoptosis in prostate cancer cells is responsible for these effects. Much of the chemopreventive effects of green tea are attributed to its major polyphenolic constituent (−) epigallocatechin-3-gallate (EGCG). In the present study, we report that EGCG-induced apoptosis in human prostate carcinoma LNCaP cells is mediated via modulation of two related pathways: (a) stabilization of p53 by phosphorylation on critical serine residues and p14ARF-mediated downregulation of murine double minute 2(MDM2) protein, and (b) negative regulation of NF-κB activity, thereby decreasing the expression of the proapoptotic protein Bcl-2. EGCG-induced stabilization of p53 caused an upregulation in its transcriptional activity, thereby resulting in activation of its downstream targets p21/WAF1 and Bax. Thus, EGCG had a concurrent effect on two important transcription factors p53 and NF-κB, causing a change in the ratio of Bax/Bcl-2 in a manner that favors apoptosis. This altered expression of Bcl-2 family members triggered the activation of initiator capsases 9 and 8 followed by activation of effector caspase 3. Activation of the caspases was followed by poly (ADP-ribose) polymerase cleavage and induction of apoptosis. Taken together, the data indicate that EGCG induces apoptosis in human prostate carcinoma cells by shifting the balance between pro- and antiapoptotic proteins in favor of apoptosis.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

Abbreviations

EGCG:

(−)-epigallocatechin-3-gallate

PARP:

poly (ADP-ribose) polymerase

Ac-DEVD-AFC:

N-acetyl-Asp-Glu-Val-Asp-AFC (7-amino-4-trifluoromethylcoumarin)

adriamycin:

ADR

MDM2:

murine double minute 2

References

  • Agarwal ML, Taylor WR, Chernov MV, Chernova OB and Stark GR . (1998). J. Biol. Chem., 273, 1–4.

  • Ahmad N, Feyes DK, Nieminen AL, Agarwal R and Mukhtar H . (1997). J. Natl. Cancer Inst., 89, 1881–1886.

  • Ahmad N, Gupta S and Mukhtar H . (2000). Arch. Biochem. Biophys., 376, 338–346.

  • Bates S and Vousden KH . (1999). Cell. mol. Life Sci., 55, 28–37.

  • Budram-Mahadeo V, Morris PJ and Latchman DS . (2002). Oncogene, 21, 6123–6131.

  • Burns TF, Bernhard EJ and El-Deiry WS . (2001). Oncogene, 20, 4601–4612.

  • Chen C, Edelstein LC and Gelinas C . (2000). Mol. Cell. Biol., 20, 2687–2695.

  • Chen ZP, Schell JB, Ho CT and Chen KY . (1998). Cancer Lett., 129, 173–179.

  • Conney AH, Lu Y, Lou Y, Xie J and Huang M . (1999). Proc. Soc. Exp. Biol. Med., 220, 229–233.

  • Dumaz N and Meek DW . (1999). EMBO J., 18, 7002–7010.

  • El-Deiry WS, Harper JW, O'Connor PM, Velculescu VE, Canman CE, Jackman J, Pietenpol JA, Burrell M, Hill DE, Wang YS, Wiman KG, Mercer WE, Kastan MB, Kohn KW, Elledge SJ, Kinzler KW and Vogelstein B . (1994). Cancer Res., 54, 1169–1174.

  • Fotedar R, Brickner H, Saadatmandin N, Rousselle T, Diederich L, Munshi A, Jung B, Reed JC and Fotedar A . (1999). Oncogene, 18, 3652–3658.

  • Gartel AL and Tyner AL . (2002). Mol. Cancer Ther., 1, 639–649.

  • Gupta S, Ahmad N, Nieminen AL and Mukhtar H . (2000). Toxicol. Appl. Pharmacol., 164, 82–90.

  • Gupta S, Hastak K, Ahmad N, Lewin JS and Mukhtar H . (2001). Proc. Natl. Acad. Sci. USA, 98, 10350–10355.

  • Gupta S, Hussain T and Mukhtar H . (2003). Arch. Biochem. Biophys., 410, 177–185.

  • Jackson MW, Lindstrom MS and Berberich SJ . (2001). J Biol. Chem., 276, 25336–25341.

  • Kubbutat MH, Jones SN and Vousden KH . (1997). Nature, 387, 299–303.

  • Kuo PL and Lin CC . (2003). J. Biomed. Sci., 10, 219–227.

  • Levites Y, Amit T, Youdim MB and Mandel S . (2002). J. Biol. Chem., 277, 30574–30580.

  • Miyashita T, Harigai M, Hanada M and Reed JC . (1994). Cancer Res., 54, 3131–3135.

  • Miyashita T and Reed JC . (1995). Cell, 80, 293–299.

  • Otsuka T, Ogo T, Eto T, Asano Y, Suganuma M and Niho Y . (1998). Life Sci., 63, 1397–1403.

  • Pianetti S, Guo S, Kavanagh KT and Sonenshein GE . (2002). Cancer Res., 62, 652–655.

  • Sheikh MS and Fornace Jr AJ . (2000). J. Cell Physiol., 182, 171–181.

  • Sherr CJ . (2001). Nat. Rev. Mol. Cell Biol., 2, 731–737.

  • Shibata MA, Yoshidome K, Shibata E, Jorcyk CL and Green JE . (2001). Cancer Gene Ther., 8, 23–35.

  • Shieh SY, Ikeda M, Taya Y and Prives C . (1997). Cell, 91, 325–334.

  • Sizemore N, Leung S and Stark GR . (1999). Mol. Cell. Biol., 19, 4798–4805.

  • Tamatani M, Che YH, Matsuzaki H, Ogawa S, Okado H, Miyake S, Mizuno T and Tohyama M . (1999). J. Biol. Chem., 274, 8531–8538.

  • Tao W and Levine AJ . (1999). Proc. Natl. Acad. Sci. USA, 96, 6937–6941.

  • Tohyama M . (1999). Biol. Chem., 274, 8531–8538.

  • Verma IM, Stevenson JK, Schwarz EM, Van Antwerp D and Miyamoto S . (1995). Genes Dev., 9, 2723–2735.

  • Vogelstein B and Kinzler KW . (2001). Nature, 412, 865–866.

  • Vogelstein B, Lane D and Levine AJ . (2000). Nature, 408, 307–310.

  • Vousden KH . (2002). Biochim. Biophys. Acta., 1602, 47–59.

  • Vousden KH and Lu X . (2002). Nat .Rev. Cancer., 2, 594–604.

  • Weber JD, Taylor LJ, Roussel MF, Sherr CJ and Bar-Sagi D . (1999). Nat. Cell. Biol., 1, 20–26.

  • Webster GA and Perkins ND . (1999). Mol. Cell. Biol., 19, 3485–3495.

  • Weisburger JH . (1999). Proc. Soc. Exp. Biol. Med., 220, 271–275.

  • Wu X and Deng Y . (2002). Front Biosci., 7, d151–d156.

  • Yang CS, Chung JY, Yang G, Chhabra SK and Lee MJ . (2000). J. Nutr., 130, 472S–478S.

  • Yang GY, Liao J, Kim K, Yurkow EJ and Yang CS . (1998). Carcinogenesis, 19611–19616.

  • Zimmermann KC, Bonzon C and Green DR . (2001). Pharmacol. Ther., 92, 57–70.

Download references

Acknowledgements

We sincerely thank Dr George Stark (Cleveland Clinic Foundation, Cleveland, OH, USA) for his suggestions, encouragement and help. This work was supported by United States Public Health Services Grant RO1 CA 78809.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hasan Mukhtar.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hastak, K., Gupta, S., Ahmad, N. et al. Role of p53 and NF-κB in epigallocatechin-3-gallate-induced apoptosis of LNCaP cells. Oncogene 22, 4851–4859 (2003). https://doi.org/10.1038/sj.onc.1206708

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206708

Keywords

This article is cited by

Search

Quick links