ANDROGEN RECEPTOR (AR): Structure & Role In Prostate Cancer

DHARMENDRA MAURYA

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INTRODUCTION The androgen receptor (AR) belong to the steroid hormone

group of nuclear receptors with the estrogen receptor (ER), glucocorticoid receptor (GR), mineralocorticoid receptor (MR) and progesterone receptor (PR).

The AR is a ligand-dependent transcription factor that controls the expression of specific genes.

The binding of the AR to its native ligands 5α-dihydrotestosterone (DHT) and testosterone initiates male sexual development and differentiation.

5α-reductase

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Male sexual differentiation fails to occur in the absence of androgens or without a functioning AR.

A complete loss of AR function in males results in complete androgen insensitivity syndrome.

SECRETION OF ANDROGEN

www.voer.edu.vn

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ANDROGEN RECEPTOR (AR)>located on long arm of X-

chromosome>110 kDa molecular wt. and 919 amino

acid long

NTD (N-terminal domain)

DBD (DNA binding

domain)

LBD (C-terminal

ligand binding domain)

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>Highly Variable>Poly-CAG & poly-GGC

>Highly conserve>promote enhancer region of AR regulating gene

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Androgen Receptor (AR): Structure & Activity

Tan et. al : Acta Pharmacologica Sinica, 2015

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Tan et. al : Acta Pharmacologica Sinica, 2015

AR and Prostate Cancer E-twenty-six (ETS) family of transcription

factor

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AR Regulated Promoter region of target gene (TMPRSS2)

Coding region of ETS Family

Approximately 50% of prostrate cancer

Upregulate the cell-cycle proliferation

Antiandrogen

Steroidal Non- steroidal

Limited clinical application due to many side effects.

Lack androgenic properties.

So, suitable for the treatment of prostrate cancer.

Compete with AR for AR binding site.

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Conclusion the most commonly diagnosed cancer among

American men and the second leading cause of cancer deaths.

On the basis of the AR and its mechanism to action on targeting cells it regulated at several places such as blocking of DHT synthesis.

On the basis of androgen structure and function we can use for the formation of several antiandrogen drugs in the treatment of prostate cancer.

The AR is still the “master regulator” of prostate cancer.

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Reference 1. MH Eileen Tan et al.,Androgen receptor: structure, role in

prostate cancer and drug discovery,Acta Pharmacologica Sinica (2015) 36: 3–23

2. Davies P, Watt K, Kelly SM, Clark C, Price NC, McEwan IJ. Consequences of poly-glutamine repeat length for the conformation and folding of the androgen receptor amino-terminal domain. J Mol Endocrinol 2008; 41: 301–14.

3. Werner R, Holterhus PM, Binder G, Schwarz HP, Morlot M, Struve D, et al. The A645D mutation in the hinge region of the human androgen receptor (AR) gene modulates AR activity, depending on the context of the polymorphic glutamine and glycine repeats. J Clin Endocrinol Metab 2006; 91: 3515–20.

4. Wang Q, Carroll JS, Brown M. Spatial and temporal recruitment of androgen receptor and its coactivators involves chromosomal looping and polymerase tracking. Mol Cell 2005; 19: 631–42.

5. Haelens A, Tanner T, Denayer S, Callewaert L, Claessens F. The hinge region regulates DNA binding, nucleartranslocation,and transactivation of the androgen receptor. Cancer Res 2007; 67: 4514–23.

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