Edited by:Mohammad Hezarkhani MD,Urologist
Board-Certified of Urology,Tehran University ,The Member of Iranian Urological Association
Madaen Hospital Tehran Iran
Tehranclinic Hospital Tehran Iran
Mohammad.hezarkhani@yahoo.com
www.Hezarkhani.blogfa.com hosted in Washington DC, United States
31,October, 2013
AKR1C3 gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. Human aldo-keto reductases (AKR) of the 1A, 1B, 1C and 1D subfamilies are involved in the pre-receptor regulation of nuclear (steroid hormone and orphan) receptors by regulating the local concentrations of their lipophilic ligands.
AKR1C3 is one of the most interesting isoforms. It was cloned from human prostate and the recombinant protein was found to function as a 3-, 17- and 20-ketosteroid reductase with a preference for the conversion of Δ4-androstene-3,17-dione to testosterone implicating this enzyme in the local production of active androgens within the prostate. Using a validated isoform specific real-time RT-PCR procedure the AKR1C3 transcript was shown to be more abundant in primary cultures of epithelial cells than stromal cells, and its expression in stromal cells increased with benign and malignant disease.
Using a validated isoform specific monoclonal Ab, AKR1C3 protein expression was also detected in prostate epithelial cells by immunoblot analysis. Immunohistochemical staining of prostate tissue showed that AKR1C3 was expressed in adenocarcinoma and surprisingly high expression was observed in the endothelial cells.
These cells are a rich source of prostaglandin G/H synthase 2 (COX-2) and vasoactive prostaglandins (PG) and thus the ability of recombinant AKR1C enzymes to act as PGF synthases was compared. AKR1C3 had the highest catalytic efficiency (kcat/Km) for the 11-ketoreduction of PGD2 to yield 9α,11β-PGF2 raising the prospect that AKR1C3 may govern ligand access to peroxisome proliferator activated receptor (PPARγ).
Activation of PPARγ is often a pro-apoptotic signal and/or leads to terminal differentiation, while 9α,11β-PGF2 is a pro-proliferative signal. AKR1C3 is potently inhibited by non-steroidal anti-inflammatory drugs suggesting that the cancer chemopreventive properties of these agents may be mediated either by inhibition of AKR1C3 or COX.
To discriminate between these effects we developed potent AKR1C inhibitors based on N-phenylanthranilic acids that do not inhibit COX-1 or COX-2. These compounds can now be used to determine the role of AKR1C3 in producing two proliferative signals in the prostate namely testosterone and 9α,11β-PGF2.
This enzyme catalyzes the reduction of prostaglandin (PG) D2, PGH2 and phenanthrenequinone (PQ), and the oxidation of 9alpha,11beta-PGF2 to PGD2.
It may have a role in controlling cell growth and/or differentiation. This gene shares high sequence identity with three other gene members and is clustered with those three genes at chromosome 10p15-p14.
Castration-resistant prostate cancer (CRPC) may occur by several mechanisms including the upregulation of androgen receptor (AR), coactivators, and steroidogenic enzymes, including aldo keto reductase 1C3 (AKR1C3). AKR1C3 converts weaker 17-keto androgenic precursors to more potent 17-hydroxy androgens and is consistently the major upregulated gene in CRPC. Current endocrine treatment for advanced prostate cancer does not result in a complete ablation of adrenal androgens.
Adrenal androgens can be metabolized by prostate cancer cells, which is one of the mechanisms associated with progression to castration-resistant prostate cancer (CRPC). Aldo-keto reductase family 1 member C3 (AKR1C3) is a steroidogenic enzyme that plays a crucial role in the conversion of adrenal androgen dehydroepiandrosterone (DHEA) into high-affinity ligands for the androgen receptor (testosterone [T] and dihydrotestosterone [DHT]).
Researchers identified unique AR-selective coactivator- and prostate cancer growth-promoting roles for AKR1C3. AKR1C3 mRNA and protein levels were upregulated in CRPC tissue, compared with benign prostate and primary prostate cancer tissue.
High AKR1C3 levels were found only in a subset of CRPC patients. AKR1C3 can be used as a biomarker for active intratumoral steroidogenesis and can be measured in biopsy or transurethral resection of the prostate specimens. DuCaP (a CRPC cell line that has high AKR1C3 expression levels) used and converted DHEA under hormone-depleted conditions into T and DHT. The DHEA-induced growth of DuCaP could be antagonized by indomethacine, an inhibitor of AKR1C3.
AKR1C3 overexpression promotes the growth of both androgen-dependent prostate cancer and CRPC xenografts, with concomitant reactivation of androgen signaling. AKR1C3 interacted with AR in prostate cancer cells, xenografts, and in human CRPC samples and was recruited to the promoter of an androgen-responsive gene. The coactivator and growth-promoting functions of AKR1C3 were inhibited by an AKR1C3-selective competitive inhibitor.
AKR1C3 is a novel AR-selective enzymatic coactivator and may represent the first of more than 200 known nuclear hormone receptor coactivators that can be pharmacologically targeted.
Abbreviations
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Adione, Δ4-androstene-3,17-dione;
-
AhR, aryl hydrocarbon receptor;
-
AKR, aldo-keto reductase;
-
3α-androstanediol, 5α-androstane-3α,17β-diol;
-
3β-androstanediol, 5α-androstane-3β,17β-diol;
-
AR, androgen receptor;
-
BP, benzo[a]pyrene;
-
BPH, benign prostatic hyperplasia;
-
CaP, prostatic cancer;
-
hCAR, human constitutive androstane receptor;
-
COX, prostaglandin G/H synthase;
-
DHT, 5α-dihydrotestosterone;
-
DOC, desoxycorticosterone;
-
ERα, estrogen receptor-α;
-
ERβ, estrogen receptor-β;
-
HRP, horseradish peroxidase;
-
MR, mineralocorticoid receptor;
-
MS, mass spectrometry;
-
NSAID, non-steroidal anti-inflammatory drugs;
-
20α-OHP, 20α-hydroxyprogesterone;
-
PBGD, porphobilinogen deaminase;
-
PAH, polycyclic aromatic hydrocarbon;
-
PG, prostaglandin;
-
PPARγ, peroxisome proliferator activated receptor;
-
PR, progesterone receptor;
-
hPXR, pregnane activated receptor;
-
RAR, retinoic acid receptor;
-
RXR, retinoid X receptor;
-
SAR, structure-activity relationships;
-
TLC, thin-layer chromatography
References:
1- Steroidogenic Enzyme AKR1C3 Is a Novel Androgen Receptor-Selective Coactivator that Promotes Prostate Cancer Growth
Muralimohan Yepuru1, Zhongzhi Wu1, Anand Kulkarni2, Feng Yin1, Christina M. Barrett1,
Juhyun Kim1, Mitchell S. Steiner1, Duane D. Miller1, James T. Dalton1, and Ramesh Narayanan1
1Preclinical Research and Development, GTx Inc.; and 2Department of Pathology, University of Tennessee Health Science Center, Memphis, Tennessee /Clin Cancer Res October 15, 2013 19; 5613
2- Aldo-keto reductase family 1 member C3 (AKR1C3) is a biomarker and therapeutic target for castration-resistant prostate cancer.
Hamid AR, Pfeiffer MJ, Verhaegh GW, Schaafsma E, Brandt A, Sweep FC, Sedelaar JP, Schalken JA./Department of Urology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands. Mol Med. 2013 Jan 22;18:1449-55. doi: 10.2119/molmed.2012.00296.
3- Aldo-keto reductase family 1 member C3 / Wikipedia, the free encyclopedia 29 September 2011
4- Aldo-keto reductase (AKR) 1C3: Role in prostate disease and the development of specific inhibitors
Trevor M. Penninga, , ,Stephan Steckelbroecka, David R. Baumana, Meredith W. Millera, Yi Jina, Donna M. Peehlb, Kar-Ming Fungc, e, Hseuh-Kung Lind/Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104-6084, USAb Department of Urology, Stanford Medical School, Stanford University, Stanford, CA 94305, USAc Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USAd Department of Urology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USAe Department of Veteran Affairs Medical Center, Oklahoma City, OK 73104, USA
Molecular and Cellular Endocrinology Volume 248, Issues 1–2, 27 March 2006, Pages 182–191
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