Human Type 3 3α-Hydroxysteroid Dehydrogenase (Aldo-Keto Reductase 1C2) and Androgen Metabolism in Prostate Cells

Abstract

Human aldo-keto reductases (AKRs) of the AKR1C subfamily function in vitro as 3-keto-, 17-keto-, and 20-ketosteroid reductases or as 3␣-, 17␤-, and 20␣-hydroxysteroid oxidases. These AKRs can convert potent sex hormones (androgens, estrogens, and progestins) into their cognate inactive metabolites or vice versa. By controlling local ligand concentration AKRs may regulate steroid hormone action at the prereceptor level. AKR1C2 is expressed in prostate, and in vitro it will catalyze the nicotinamide adenine dinucleotide (NAD ؉ )-dependent oxidation of 3␣-androstanediol (3␣-diol) to 5␣-dihydrotestosterone (5␣-DHT). This reaction is potently inhibited by reduced NAD phosphate (NADPH), indicating that the NAD ؉ : NADPH ratio in cells will determine whether AKR1C2 makes 5␣-DHT. In transient COS-1-AKR1C2 and in stable PC-3-AKR1C2 transfectants, 5␣-DHT was reduced by AKR1C2. However, the transfected AKR1C2 oxidase activity was insufficient to surmount the endogenous 17␤-hydroxysteroid dehydrogenase (17␤-HSD) activity, which eliminated 3␣-diol as androsterone. PC-3 cells expressed retinol dehydrogenase/3␣-HSD and 11-cis-retinol dehydrogenase, but these endogenous enzymes did not oxidize 3␣-diol to 5␣-DHT. In stable LNCaP-AKR1C2 transfectants, AKR1C2 did not alter androgen metabolism due to a high rate of glucuronidation. In primary cultures of epithelial cells, high levels of AKR1C2 transcripts were detected in prostate cancer, but not in cells from normal prostate. Thus, in prostate cells AKR1C2 acts as a 3-ketosteroid reductase to eliminate 5␣-DHT and prevents activation of the androgen receptor. AKR1C2 does not act as an oxidase due to either potent product inhibition by NADPH or because it cannot surmount the oxidative 17␤-HSD present. Neither AKR1C2, retinol dehydrogenase/3␣-HSD nor 11-cis-retinol dehydrogenase is a source of 5␣-DHT in PC-3 cells.

Increased expression of type 2 3α-hydroxysteroid dehydrogenase/type 5 17β-hydroxysteroid dehydrogenase (AKR1C3) and its relationship with androgen receptor in prostate carcinoma

“…We conclude that AKR1C3 is upregulated in CaP. Increased AKR1C3 immunoreactivity in adenocarcinoma cells is in accord with our previous observation that elevated reductive 3a-HSD enzymes, such as AKR1C2 (Rizner et al 2003) and ARK1C3 (Lin et al 1997) show increased transcript expression in primary cultures of prostate epithelial cells derived from cancerous sections of the prostate.…”

5α-Androstane-3α,17β-diol activates pathway that resembles the epidermal growth factor responsive pathways in stimulating human prostate cancer LNCaP cell proliferation

“…Therefore, accumulation of 3a-diol in the prostate through the actions of 3a-HSDs 41,42 and 17b-HSD 42,43 may be partially responsible for the pathogenesis of prostatic diseases. Upregulated expression of 3a-HSD transcripts 41 in primary cultures of prostate cells derived from BPH and PCa and proteins (unpublished results) in BPH and PCa tissue sections may account for 3a-diol accumulation in the diseased gland. It is possible that failure of initial treatment modality and further clinical progression of BPH and PCa may result from augmentation of both 5a-DHT and 3a-diol and imbalance of androgen-metabolizing enzymes in the diseased prostate.…”

Primary cell cultures as models of prostate cancer development

“…AKR1C2 (type 3 3a-hydroxysteroid dehydrogenase) is expressed in the prostate. In primary cultures, high levels of AKR1C2 were found in cancer but not normal cells (Rizner et al 2003). This finding, together with metabolic studies in prostate cancer cell lines, suggests that in prostate cancer cells, AKR1C2 acts as a 3-ketosteroid reductase to eliminate DHT, and thereby reduce activation of the AR.…”