Advertisement

Molecular Medicine

, Volume 18, Issue 11, pp 1449–1455 | Cite as

Aldo-keto Reductase Family 1 Member C3 (AKR1C3) Is a Biomarker and Therapeutic Target for Castration-Resistant Prostate Cancer

  • Agus Rizal A. H. Hamid
  • Minja J. Pfeiffer
  • Gerald W. Verhaegh
  • Ewout Schaafsma
  • Andre Brandt
  • Fred C. G. J. Sweep
  • John P. M. Sedelaar
  • Jack A. Schalken
Research Article

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.

Notes

Acknowledgments

We thank Cornelius F Jansen, Tilly W Aalders, Alexandra Dudek and Mirjam de Weijert for excellent laboratory support. This work was part of the Cancer Cure Early Stage Research Training (CANCURE) and Prostate Research Organizations-Network of Early Stage Training (PRO-NEST) project funded by the European Commission FP7 Marie Curie Initial Training Networks (ITN) (contract 238278).

Supplementary material

10020_2012_18111449_MOESM1_ESM.pdf (346 kb)
Supplementary material, approximately 346 KB.

References

  1. 1.
    Lee DJ, et al. (2012) Novel therapeutics for the management of castration-resistant prostate cancer (CRPC). BJU Int. 109:968–85.CrossRefGoogle Scholar
  2. 2.
    Tsao CK, Galsky MD, Small AC, Yee T, Oh WK. (2012). Targeting the androgen receptor signalling axis in castration-resistant prostate cancer (CRPC). BJU Int. 110:1580–8.CrossRefGoogle Scholar
  3. 3.
    Aggarwal R, Ryan CJ. (2011) Castration-resistant prostate cancer: targeted therapies and individualized treatment. Oncologist. 16:264–75.CrossRefGoogle Scholar
  4. 4.
    Mottet N, et al. (2011) EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur. Urol. 59:572–83.CrossRefGoogle Scholar
  5. 5.
    Nishiyama T, Hashimoto Y, Takahashi K. (2004) The influence of androgen deprivation therapy on dihydrotestosterone levels in the prostatic tissue of patients with prostate cancer. Clin. Cancer Res. 10:7121–6.CrossRefGoogle Scholar
  6. 6.
    Mohler JL, et al. (2004) The androgen axis in recurrent prostate cancer. Clin. Cancer Res. 10:440–8.CrossRefGoogle Scholar
  7. 7.
    Titus MA, Schell MJ, Lih FB, Tomer KB, Mohler JL. (2005) Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin. Cancer Res. 11:4653–7.CrossRefGoogle Scholar
  8. 8.
    Hofland J, et al. (2010) Evidence of limited contributions for intratumoral steroidogenesis in prostate cancer. Cancer Res. 70:1256–64.CrossRefGoogle Scholar
  9. 9.
    Locke JA, et al. (2008) Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 68:6407–15.CrossRefGoogle Scholar
  10. 10.
    Montgomery RB, et al. (2008) Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 68:4447–54.CrossRefGoogle Scholar
  11. 11.
    Stanbrough M, et al. (2006) Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 66:2815–25.CrossRefGoogle Scholar
  12. 12.
    Mizokami A, et al. (2009) Prostate cancer stromal cells and LNCaP cells coordinately activate the androgen receptor through synthesis of testosterone and dihydrotestosterone from dehydroepiandrosterone. Endocr. Relat. Cancer. 16:1139–55.CrossRefGoogle Scholar
  13. 13.
    Tran C, et al. (2009) Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 324:787–90.CrossRefGoogle Scholar
  14. 14.
    Attard G, Reid AH, Olmos D, de Bono JS. (2009) Antitumor activity with CYP17 blockade indicates that castration-resistant prostate cancer frequently remains hormone driven. Cancer Res. 69:4937–40.CrossRefGoogle Scholar
  15. 15.
    Pfeiffer MJ, Smit FP, Sedelaar JP, Schalken JA. (2011) Steroidogenic enzymes and stem cell markers are upregulated during androgen deprivation in prostate cancer. Mol. Med. 17:657–64.CrossRefGoogle Scholar
  16. 16.
    De Kok JB, et al. (2005) Normalization of gene expression measurements in tumor tissues: comparison of 13 endogenous control genes. Lab. Invest. 85:154–9.CrossRefGoogle Scholar
  17. 17.
    Pfaffl MW. (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 29:e45.CrossRefGoogle Scholar
  18. 18.
    Azzarello J, Fung KM, Lin HK. (2008) Tissue distribution of human AKR1C3 and rat homolog in the adult genitourinary system. J. Histochem. Cytochem. 56:853–1.CrossRefGoogle Scholar
  19. 19.
    Kogan I, et al. (2006) hTERT-immortalized prostate epithelial and stromal-derived cells: an authentic in vitro model for differentiation and carcinogenesis. Cancer Res. 66:3531–40.CrossRefGoogle Scholar
  20. 20.
    Pfeiffer MJ, Mulders PF, Schalken JA. (2010) An in vitro model for preclinical testing of endocrine therapy combinations for prostate cancer. Prostate. 70:1524–32.CrossRefGoogle Scholar
  21. 21.
    Klein KA, et al. (1997) Progression of metastatic human prostate cancer to androgen independence in immunodeficient SCID mice. Nat. Med. 3:402–8.CrossRefGoogle Scholar
  22. 22.
    Nishiyama T, Ikarashi T, Hashimoto Y, Wako K, Takahashi K. (2007) The change in the dihydrotestosterone level in the prostate before and after androgen deprivation therapy in connection with prostate cancer aggressiveness using the Gleason score. J. Urol. 178:1282–8.CrossRefGoogle Scholar
  23. 23.
    Swinkels LM, Ross HA, Smals AG, Benraad TJ. (1990) Concentrations of total and free dehydroepiandrosterone in plasma and dehydroepiandrosterone in saliva of normal and hirsute women under basal conditions and during administration of dexamethasone/synthetic corticotropin. Clin. Chem. 36:2042–6.PubMedGoogle Scholar
  24. 24.
    Swinkels LM, van Hoof HJ, Ross HA, Smals AG, Benraad TJ. (1992) Low ratio of androstenedione to testosterone in plasma and saliva of hirsute women. Clin. Chem. 38:1819–23.PubMedGoogle Scholar
  25. 25.
    Swinkels LM, van Hoof HJ, Ross HA, Smals AG, Benraad TJ. (1991) Concentrations of salivary testosterone and plasma total, non-sex-hormone-binding globulin-bound, and free testosterone in normal and hirsute women during administration of dexamethasone/synthetic corticotropin. Clin. Chem. 37:180–5.PubMedGoogle Scholar
  26. 26.
    Byrns MC, Steckelbroeck S, Penning TM. (2008) An indomethacin analogue, N-(4-chlorobenzoyl)-melatonin, is a selective inhibitor of aldo-keto reductase 1C3 (type 2 3alpha-HSD, type 5 17beta-HSD, and prostaglandin F synthase), a potential target for the treatment of hormone dependent and hormone independent malignancies. Biochem. Pharmacol. 75:484–93.CrossRefGoogle Scholar
  27. 27.
    Sedelaar JP, Isaacs JT. (2009) Tissue culture media supplemented with 10% fetal calf serum contains a castrate level of testosterone. Prostate. 69:1724–9.CrossRefGoogle Scholar
  28. 28.
    van Bokhoven A, et al. (2003) Molecular characterization of human prostate carcinoma cell lines. Prostate. 57:205–25.CrossRefGoogle Scholar
  29. 29.
    Byrns MC, Mindnich R, Duan L, Penning TM. (2012) Overexpression of aldo-keto reductase 1C3 (AKR1C3) in LNCaP cells diverts androgen metabolism towards testosterone resulting in resistance to the 5alpha-reductase inhibitor finasteride. J. Steroid. Biochem. Mol. Biol. 130:7–15.CrossRefGoogle Scholar
  30. 30.
    Wlodkowic D, Skommer J, Darzynkiewicz Z. (2012) Cytometry of apoptosis: historical perspective and new advances. Exp. Oncol. 34:255–62.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Wako K, et al. (2008) Expression of androgen receptor through androgen-converting enzymes is associated with biological aggressiveness in prostate cancer. J. Clin. Pathol. 61:448–54.CrossRefGoogle Scholar
  32. 32.
    Kohli M, Tindall DJ. (2010) New developments in the medical management of prostate cancer. Mayo Clin. Proc. 85:77–86.CrossRefGoogle Scholar
  33. 33.
    Adeniji AO, et al. (2012) Development of potent and selective inhibitors of aldo-keto reductase 1C3 (type 5 17beta-hydroxysteroid dehydrogenase) based on N-phenyl-aminobenzoates and their structure-activity relationships. J. Med. Chem. 55:2311–23.CrossRefGoogle Scholar
  34. 34.
    Brozic P, et al. (2012) Selective inhibitors of aldoketo reductases AKR1C1 and AKR1C3 discovered by virtual screening of a fragment library. J. Med. Chem. 55:7417–24.CrossRefGoogle Scholar
  35. 35.
    Chen M, et al. (2012) Crystal structures of AKR1C3 containing an N-(aryl)amino-benzoate inhibitor and a bifunctional AKR1C3 inhibitor and androgen receptor antagonist: therapeutic leads for castrate resistant prostate cancer. Bioorg. Med. Chem. Lett. 22:3492–7.CrossRefGoogle Scholar
  36. 36.
    Jamieson SM, et al. (2012) 3-(3,4-Dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic acids: highly potent and selective inhibitors of the type 5 17-beta-hydroxysteroid dehydrogenase AKR1C3. J. Med. Chem. 55:7746–58.CrossRefGoogle Scholar
  37. 37.
    Attard G, et al. (2012) Clinical and biochemical consequences of CYP17A1 inhibition with abiraterone given with and without exogenous glucocorticoids in castrate men with advanced prostateGoogle Scholar

Copyright information

© The Author(s) 2012

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (https://doi.org/creativecommons.org/licenses/by-nc-nd/4.0/)

Authors and Affiliations

  • Agus Rizal A. H. Hamid
    • 1
    • 2
    • 3
  • Minja J. Pfeiffer
    • 1
    • 3
  • Gerald W. Verhaegh
    • 1
    • 3
  • Ewout Schaafsma
    • 4
  • Andre Brandt
    • 5
  • Fred C. G. J. Sweep
    • 5
  • John P. M. Sedelaar
    • 1
  • Jack A. Schalken
    • 1
    • 3
    • 6
  1. 1.Department of UrologyRadboud University Nijmegen Medical CentreNijmegenNetherlands
  2. 2.Department of Urology, Ciptomangunkusumo Hospital, and Department of Surgery, Faculty of MedicineUniversity of IndonesiaJakartaIndonesia
  3. 3.Nijmegen Center for Molecular Life SciencesNijmegenNetherlands
  4. 4.Department of PathologyRadboud University Nijmegen Medical CenterNijmegenNetherlands
  5. 5.Department of Laboratory MedicineRadboud University Nijmegen Medical CenterNijmegenNetherlands
  6. 6.267 Experimental UrologyRadboud University Nijmegen Medical CentreNijmegenNetherlands

Personalised recommendations