Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Jan 22;18(1):1449-55.
doi: 10.2119/molmed.2012.00296.

Aldo-keto reductase family 1 member C3 (AKR1C3) is a biomarker and therapeutic target for castration-resistant prostate cancer

Agus Rizal A H Hamid  1 , Minja J Pfeiffer, Gerald W Verhaegh, Ewout Schaafsma, Andre Brandt, Fred C G J Sweep, John P M Sedelaar, Jack A Schalken
Affiliations

Aldo-keto reductase family 1 member C3 (AKR1C3) is a biomarker and therapeutic target for castration-resistant prostate cancer

Agus Rizal A H Hamid et al. Mol Med. .

Abstract

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]). The aim of this study was to examine whether AKR1C3 could be used as a marker and therapeutic target for CRPC. 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. This study indicates that AKR1C3 can be considered a therapeutic target in a subgroup of patients with high AKR1C3 expression.

PubMed Disclaimer

Figures

Figure 1
Figure 1
AKR1C3 expression in clinical samples. (A) Relative AKR1C3 mRNA expression in tissue samples. AKR1C3 qPCR data were normalized to the HPRT housekeeping gene levels. (B) Example of AKR1C3 Western blot analysis using protein extracts derived from fresh-frozen tissue specimens. β-Actin was used for normalization purposes; the ratio of AKR1C3/β-actin expression was determined after optical scanning of the Western blots. One primary PCa case was used as a reference (ratio set to 1). (C) AKR1C3 immunohistochemistry of a primary PCa specimen with weak AKR1C3 staining (image 1) and three CRPC specimens with different AKR1C3 staining intensities: strong (image 2), weak/intermediate (image 3) and negative (image 4). For technical details, see text.
Figure 2
Figure 2
AKR1C3 levels in several prostate (cancer) cell lines. AKR1C3 protein levels in cell lines were determined by Western blot analysis. β-Actin was used for normalization.
Figure 3
Figure 3
DHEA-induced DuCaP proliferation. (A) Schematic illustration of the metabolic conversion of DHEA into T and DHT. (B) DuCaP cell proliferation in medium, supplemented with different concentrations of DHEA. Cells were grown for 16 d; then the fraction of viable cells was determined using MTT assays and normalized to cells grown in d 0. Each experiment was done in triplicate. Statistical analysis was performed by using one-way ANOVA, Dunnett correction test. *p < 0.05. (C) DuCaP cell proliferation in 100 nmol/L DHEA-containing medium. Each experiment was done in triplicate. Statistical analysis was performed by using two-way ANOVA, Bonferroni correction test. **p < 0.001. (D) Androgen levels measured in conditioned medium of DuCaP cells growing in medium supplemented with 100 nmol/L DHEA. (E) AKR1C3 protein expression measured by Western blot in DuCaP cells cultured for the indicated times in medium supplemented with 100 nmol/L DHEA. Statistical analysis was performed by using one-way ANOVA, Dunnett correction test. *p < 0.05. (A–E) All experiments were performed at least two times. Standard error of the means are indicated by bars.
Figure 4
Figure 4
INN inhibits DuCaP proliferation through interference with DHEA conversion resulting in the induction of apoptosis. (A) Inhibition of DuCaP cell proliferation by adding INN. Each experiment was done in triplicate. ◆, CSS only/no steroid; ●, CSS + 100 nmol/L DHEA; ■ CSS + DHEA + 10 μmol/L INN; ▲, CSS + DHEA + 25 μmol/L INN. Statistical analysis was performed by using two-way ANOVA, Bonferroni correction test, compared with the CSS + DHEA group. **p < 0.001. (B) Reduction of androgen levels upon treatment of DuCaP cells with INN. Androgen levels were measured at d 16. Statistical analysis was performed by using one-way ANOVA, Dunnett correction test. *p < 0.05. Standard error of the means are indicated by bars. (C) Apo-ONE caspase-3/7 assay showed that INN treatment for 2 h induces cell apoptosis in a dose-dependent manner. Statistical analysis was performed by using one-way ANOVA, Dunnett correction test. *p < 0.05. (D) Flow cytometry of propidium iodide–stained DuCaP cells treated with INN for 48 h. Black line: CSS + 100 nmol/L DHEA; blue line: CSS + DHEA + 10 μmol/L INN; red line: CSS + DHEA + 25 μmol/L INN. Arrow: sub-G1 apoptotic cell population. All experiments were performed at least two times.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Lee DJ, et al. Novel therapeutics for the management of castration-resistant prostate cancer (CRPC) BJU Int. 2012;109:968–85. - PubMed
    1. Tsao CK, Galsky MD, Small AC, Yee T, Oh WK. Targeting the androgen receptor signalling axis in castration-resistant prostate cancer (CRPC) BJU Int. 2012;110:1580–8. - PubMed
    1. Aggarwal R, Ryan CJ. Castration-resistant prostate cancer: targeted therapies and individualized treatment. Oncologist. 2011;16:264–75. - PMC - PubMed
    1. Mottet N, et al. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2011;59:572–83. - PubMed
    1. Nishiyama T, Hashimoto Y, Takahashi K. The influence of androgen deprivation therapy on dihydrotestosterone levels in the prostatic tissue of patients with prostate cancer. Clin Cancer Res. 2004;10:7121–6. - PubMed

Publication types

MeSH terms