Disease relevance of AKR1C2

• Selective loss of AKR1C1 and AKR1C2 in breast cancer and their potential effect on progesterone signaling [1].
• Selective reduction of AKR1C2 in prostate cancer and its role in DHT metabolism [2].
• These data indicated that AKR1C2 expression could be significantly associated with cancer invasiveness (p<0.001) and disease progression [3].
• Among AKR1C2-positive UBC, 148 (65.5%) were invasive, 70 (31.0%) were non-invasive and 8 (3.5%) were carcinoma in situ (CIS) [3].
• BACKGROUND/AIMS: The investigation is to understand whether polypeptide growth factor NUN can enhance AKR1C2 transcriptional expression in human SMMC7721 liver cancer cell line or not [4].

High impact information on AKR1C2

• Phenyl ketone 1 is a cell-permeable fluorogenic probe that permits a direct, real-time, and operationally simple readout of AKR1C2 enzyme activity in intact mammalian cells [5].
• The high selectivity of phenyl ketone 1 for AKR1C2 over the many endogenous reductases present in mammalian cells was established by a quantitative comparison of the metabolic rates between null control cells (COS-1) and AKR1C2-transfected cells [5].
• Fluorogenic metabolic probes for direct activity readout of redox enzymes: Selective measurement of human AKR1C2 in living cells [5].
• Moreover, treatment of AREc32 cells with BSO immediately before exposure to anticancer drugs enhanced induction of ARE-driven luciferase activity by cisplatin, BCNU, chlorambucil, and melphalan and also induced endogenous AKR1C (AKR1C refers to AKR1C1 and AKR1C2), a target gene of Nrf2 [6].
• Suppression of AKR1C1 alone or with AKR1C2 in T-47D cells led to decreased growth in the presence of progesterone [1].

Chemical compound and disease context of AKR1C2

• Role of human type 3 3alpha-hydroxysteroid dehydrogenase (AKR1C2) in androgen metabolism of prostate cancer cells [7].
• In androgen dependent human prostate cancer cells LNCaP, it was not possible to ascertain the preferred direction of AKR1C2 by stable transfection due to the high rate of 5alpha-DHT and 3alpha-diol glucuronidation [7].
• OBJECTIVES: The aim of the present study was to investigate the association between the homozygous DD (deletion) genotype of the angiotensin-converting enzyme gene and survival and cardiac function in patients with idiopathic congestive heart failure [8].
• The cytotoxicity of several PAH o-quinones derived from this reaction [naphthalene-1,2-dione (NPQ), benzo[a]pyrene-7,8-dione (BPQ), and 7,12-dimethylbenz[a]anthracene-3,4-dione (DMBAQ)] was examined in rat (H-4IIe) and human (Hep-G2) hepatoma cells which are known to express DD [9].
• Retention factors on the immobilized artificial membrane column (IAM PC DD 2) with 10% (v/v) methanol-water as mobile phase are able to estimate non-specific toxicity to the fathead minnow with a standard error (SE) of 0.22 log units and coefficient of determination (r2) of 0.97 for 31 compounds [10].

Biological context of AKR1C2

• Sequence of the cDNA of a human dihydrodiol dehydrogenase isoform (AKR1C2) and tissue distribution of its mRNA [11].
• However, four cDNA species with more than 99% sequence identity have been cloned and are compatible with a partial amino acid sequence of DD2 [11].
• Charon 4A and P1 genomic clones contained at least three rat genes (type 1, type 2 and type 3 3alpha-HSD/DD) each of which encoded for the same open reading frame (ORF) but differed in their exon-intron organization [12].
• Transient transfection with Nrf2 increased the transcriptional activity of the ARE of AKR1C2 comparable with that observed with phase II inducers [13].
• Induction of AKR1C2 by phase II inducers: identification of a distal consensus antioxidant response element regulated by NRF2 [13].

Anatomical context of AKR1C2

• Normal astrocytes exposed to elevated hydrostatic pressure selectively increased AKR1C2 expression [14].
• RESULTS: AKR1C2 preferentially reduces DHT to the weak metabolite 5 alpha-androstane-3 alpha,17 beta-diol (3 alpha-diol) without conversion of 3 alpha-diol to DHT in the PC-3 cell line, and its expression was increased by DHT treatment in LNCaP cells [2].
• AKR1C2 mRNA and 5alpha-DHT inactivation were detected in both s.c. and Om adipose tissue [15].
• We examined 5alpha-dihydrotestosterone (5alpha-DHT) inactivation and the expression of several steroid-converting enzymes with a focus on aldoketoreductases 1C (AKR1C), especially AKR1C2, in abdominal adipose tissue in men [15].
• AKR1C4 is virtually liver specific, while AKR1C2 and AKR1C3 are dominantly expressed in prostate and mammary gland [16].

Associations of AKR1C2 with chemical compounds

• Suppression of ARK1C1 and AKR1C2 by selective small interfering RNAs inhibited production of 20alpha-dihydroprogesterone and was associated with increased progesterone in MCF-10A cells [1].
• Furthermore, strong substrate inhibition was observed for the AKR1C2 catalyzed reduction of tibolone [17].
• AKR1C2 is mainly involved in the conversion of the potent androgen 5alpha-DHT to its inactive forms 5alpha-androstane-3alpha/beta,17beta-diol (3alpha/beta-diol) [15].
• Genomic structure of rat 3alpha-hydroxysteroid/dihydrodiol dehydrogenase (3alpha-HSD/DD, AKR1C9) [12].
• The k(cat) for the NADPH-dependent reduction of DHT catalyzed by AKR1C2 is 0.033 s(-1) [18].

Enzymatic interactions of AKR1C2

• In mammalian transfection studies all enzymes except AKR1C2 oxidized 3alpha-diol back to DHT where RODH 5, RODH 4, and RL-HSD were the most efficient [19].

Regulatory relationships of AKR1C2

• Growth factor NUN increased AKR1C2 expression by activated CDK2 related RB signal transduction pathway in human liver cancer cell line [4].
• Based on these findings AKR1C2 may diminish 5alpha-DHT and prevent this ligand from activating the androgen receptor in situ [7].

Other interactions of AKR1C2

• Promoter activities of the 20alpha-HSD, BABP and PGFS genes were high, both in ovarian granulosa cells and hepatocytes [20].
• Using NAD+, the 3-hydroxymetabolites were efficiently oxidized by homogeneous recombinant AKR1C2 and AKR1C4 [17].
• Whereas AKR1C2 acted as a 3alpha-HSD toward 5alpha-DHT, it functioned exclusively as a 3beta-HSD on tibolone [17].
• To determine whether AKR1C2 preferentially functions as a reductase or an oxidase in a cellular context, we transiently transfected AKR1C2 (pcDNA3-AKR1C2) into COS-1 cells and stably transfected pcDNA3-AKR1C2 and pLNCX-AKR1C2 constructs into PC-3 and LNCaP cells, respectively [7].
• RT-PCR analysis demonstrated the expression of 5 alpha-reductase type 1, 5 beta-reductase, aldo-keto-reductase (AKR) 1C1, AKR1C2, AKR1C3, 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) type 2, and 17 alpha-hydroxylase/17,20-lyase (P450c17) [21].

Analytical, diagnostic and therapeutic context of AKR1C2

• To determine why AKR1C2 has a much lower k(cat) than AKR1C9, the events associated with the binding of cofactor to both enzymes were studied by steady state fluorescence titration and stopped-flow experiments [22].
• These cells lysates were prepared to examine AKR1C2 expression by Western blot [4].
• Total RNA was extracted from these cells to analyze the change of AKR1C2 mRNA by Northern blot [4].
• In the present study we performed site-directed mutagenesis of the seven residues (Thr-38, Arg-47, Leu-54, Cys-87, Val-151, Arg-170 and Gln-172) of DD1 to the corresponding residues (Val, His, Val, Ser, Met, His and Leu respectively) of DD2 [23].
• Increased expression of the potential proapoptotic molecule DD2 and increased synthesis of leukotriene B4 during allograft rejection in a marine sponge [24].

References