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Review
. 2020 Feb:196:105499.
doi: 10.1016/j.jsbmb.2019.105499. Epub 2019 Oct 12.

Intracrinology-revisited and prostate cancer

Trevor M Penning  1 , Andrea J Detlefsen  2
Affiliations
Review

Intracrinology-revisited and prostate cancer

Trevor M Penning et al. J Steroid Biochem Mol Biol. 2020 Feb.

Abstract

The formation of steroid hormones in peripheral target tissues is referred to as their intracrine formation. This process occurs in hormone dependent malignancies such as prostate and breast cancer in which the disease can be either castrate resistant or occur post-menopausally, respectively. In these instances, the major precursor steroid of androgens and estrogens is dehydroepiandrosterone (DHEA) and DHEA-SO4. This article reviews the major pathways by which adrenal steroids are converted to the potent male sex hormones, testosterone (T) and 5α-dihydrotestosterone (5α-DHT) and the discrete enzyme isoforms involved in castration resistant prostate cancer. Previous studies have mainly utilized radiotracers to investigate these pathways but have not used prevailing concentrations of precursors found in castrate male human serum. In addition, the full power of stable-isotope dilution liquid chromatography tandem mass spectrometry has not been applied routinely. Furthermore, it is clear that adaptive responses occur in the transporters and enzyme isoforms involved in response to androgen deprivation therapy that need to be considered.

Keywords: Abiraterone acetate; Aldo-Keto reductase; Androgen receptor; Androgens; Bicalutamide; Castration resistant prostate cancer; Enzalutamide; Hydroxysteroid dehydrogenase; Leuprolide; Steroid 5α-reductase.

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Figures

Figure 1.
Figure 1.
Androgen metabolism in human prostate. The canonical pathway is shown in red; the alternative pathway is shown in blue; the backdoor pathway is shown in pink; and the pathway from 5-androstenediol is shown in black. Enzymes are identified by their gene names which are italicized.
Figure 2.
Figure 2.
11-Oxo-Androgens. Formation of 11-oxo-T and 11-oxo-DHT from their 11β-hydroxysteroid precursors. Enzymes are identified by their gene names which are italicized.
Fig 3.
Fig 3.
Overexpression of AKR1C3 in CRPC. RT-PCR, and Affymetrix microarray detection of AKR1C3 RNA expression in normal prostate (Pr) and androgen-independent prostate cancer (AIPCa-also known as castration resistant prostate cancer, CRPC), Panel A; specificity of murine anti-human AKR1C3 antibody for recombinant AKR1C3 versus its highly related isoforms AKR1C1, AKR1C2 and AKR1C4, Panel B; immunohistochemical detection of AKR1C3 in CRPC (top left) and staining with pre-immune serum (top-right); immunohistochemical detection of AKR1C3 in soft tissue metastatic tissue, (bottom left) and staining with pre-immune serum (bottom right); Taken from references (43,67).
Fig. 4.
Fig. 4.
Position of nsSNPs in the AKR1C3 crystal structure. NADP+ (green); indomethacin, a competitive inhibitor (magenta), nsSNPs (in red), Calpha-chain in blue. Created in PyMol. Taken from PDB 1S2A
See this image and copyright information in PMC

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