Green tea polyphenol EGCG blunts androgen receptor function in prostate cancer

Imtiaz A. Siddiqui, Mohammad Asim, Bilal Hafeez, Vaqar M. Adhami, Rohinton S. Tarapore, Hasan Mukhtar

Research output: Contribution to journalArticle

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Abstract

Androgen deprivation therapy is the major treatment for advanced prostate cancer (PCa). However, it is a temporary remission, and the patients almost inevitably develop hormone refractory prostate cancer (HRPC). HRPC is almost incurable, although most HRPC cells still express androgen receptor (AR) and depend on the AR for growth, making AR a prime drug target. Here, we provide evidence that epigallocatechin-3-gallate (EGCG), the major polyphenol in green tea, is a direct antagonist of androgen action. In silico modeling and FRET-based competition assay showed that EGCG physically interacts with the ligandbinding domain of AR by replacing a high-affinity labeled ligand (IC 50 0.4 mu;M). The functional consequence of this interaction was a decrease in AR-mediated transcriptional activation, which was due to EGCG mediated inhibition of interdomain N-C termini interaction of AR. Treatment with EGCG also repressed the transcriptional activation by a hotspot mutant AR (T877A) expressed ectopically as well as the endogenous AR mutant. As the physiological consequence of AR antagonism, EGCG repressed R1881-induced PCa cell growth. In a xenograft model, EGCG was found to inhibit AR nuclear translocation and protein expression. We also observed a significant down-regulation of androgen-regulated miRNA-21 and up-regulation of a tumor suppressor, miRNA-330, in tumors of mice treated with EGCG. Taken together, we provide evidence that EGCG functionally antagonizes androgen action at multiple levels, resulting in inhibition of PCa growth.

Original languageEnglish (US)
Pages (from-to)1198-1207
Number of pages10
JournalFASEB Journal
Volume25
Issue number4
DOIs
StatePublished - Apr 1 2011

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Androgen Receptors
Polyphenols
Tea
Prostatic Neoplasms
Refractory materials
Androgens
Hormones
MicroRNAs
Transcriptional Activation
Tumors
Growth
Chemical activation
Metribolone
epigallocatechin gallate
Androgen Antagonists
Cell growth
Nuclear Proteins
Heterografts
Computer Simulation
Assays

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Siddiqui, I. A., Asim, M., Hafeez, B., Adhami, V. M., Tarapore, R. S., & Mukhtar, H. (2011). Green tea polyphenol EGCG blunts androgen receptor function in prostate cancer. FASEB Journal, 25(4), 1198-1207. https://doi.org/10.1096/fj.10-167924

Green tea polyphenol EGCG blunts androgen receptor function in prostate cancer. / Siddiqui, Imtiaz A.; Asim, Mohammad; Hafeez, Bilal; Adhami, Vaqar M.; Tarapore, Rohinton S.; Mukhtar, Hasan.

In: FASEB Journal, Vol. 25, No. 4, 01.04.2011, p. 1198-1207.

Research output: Contribution to journalArticle

Siddiqui, IA, Asim, M, Hafeez, B, Adhami, VM, Tarapore, RS & Mukhtar, H 2011, 'Green tea polyphenol EGCG blunts androgen receptor function in prostate cancer', FASEB Journal, vol. 25, no. 4, pp. 1198-1207. https://doi.org/10.1096/fj.10-167924
Siddiqui, Imtiaz A. ; Asim, Mohammad ; Hafeez, Bilal ; Adhami, Vaqar M. ; Tarapore, Rohinton S. ; Mukhtar, Hasan. / Green tea polyphenol EGCG blunts androgen receptor function in prostate cancer. In: FASEB Journal. 2011 ; Vol. 25, No. 4. pp. 1198-1207.
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