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Pippione et al. J Cancer Metastasis Treat 2017;3:328-61 Journal of
DOI: 10.20517/2394-4722.2017.44
Cancer Metastasis and Treatment

www.jcmtjournal.com
Topic: How does the prostate cancer microenvironment affect the metastatic Open Access
process and/or treatment outcome?

Androgen-AR axis in primary and metastatic

prostate cancer: chasing steroidogenic

enzymes for therapeutic intervention

Agnese C. Pippione , Donatella Boschi , Klaus Pors , Simonetta Oliaro-Bosso , Marco L. Lolli 1
1
2
1
1
1 Department of Science and Drug Technology, University of Torino, 10125 Torino, Italy.
2 Institute of Cancer Therapeutics, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UK.
Correspondence to: Dr. Marco L. Lolli, Department of Science and Drug Technology, University of Torino, Via Pietro Giuria 9, 10125 Torino, Italy.
E-mail: marco.lolli@unito.it; Dr. Simonetta Oliaro-Bosso, Department of Science and Drug Technology, University of Torino, Via Pietro Giuria 9, 10125
Torino, Italy. E-mail: simona.oliaro@unito.it
How to cite this article: Pippione AC, Boschi D, Pors K, Oliaro-Bosso S, Lolli ML. Androgen-AR axis in primary and metastatic prostate cancer:
chasing steroidogenic enzymes for therapeutic intervention. J Cancer Metastasis Treat 2017;3:328-61.

ABSTRACT
Article history: Androgens play an important role in prostate cancer (PCa) development and progression.
Received: 21 Jun 2017 Although androgen deprivation therapy remains the front-line treatment for advanced
First Decision: 16 Aug 2017 prostate cancer, patients eventually relapse with the lethal form of the disease. The prostate
Revised: 4 Sep 2017 tumor microenvironment is characterised by elevated tissue androgens that are capable of
Accepted: 26 Oct 2017 activating the androgen receptor (AR). Inhibiting the steroidogenic enzymes that play vital
Published: 12 Dec 2017 roles in the biosynthesis of testosterone (T) and dihydrotestosterone (DHT) seems to be an
attractive strategy for PCa therapies. Emerging data suggest a role for the enzymes mediating
Key words: pre-receptor control of T and DHT biosynthesis by alternative pathways in controlling
AKR1C3, intratumoral androgen levels, and thereby influencing PCa progression. This supports the
HSD17B3, idea for the development of multi-targeting strategies, involving both dual and multiple
CYP17A1, inhibitors of androgen-metabolising enzymes that are able to affect androgen synthesis and
SRD5A, signalling at different points in the biosynthesis. In this review, we will focus on CYP17A1,
androgen receptor, AKR1C3, HSD17B3 and SRD5A, as these enzymes play essential roles in all the three
castration-resistant prostate cancer, androgenic pathways. We will review also the AR as an additional target for the design of
inhibitors, bifunctional drugs. Targeting intracrine androgens and AKR1C3 have potential to overcome
bifunctional molecules enzalutamide and abiraterone resistance and improve survival of advanced prostate cancer
patients.

INTRODUCTION prostate growth and function by interacting with
the androgen receptor (AR), drive PCa growth and
[2]
Prostate cancer (PCa) is the most commonly play a central role in PCa progression . Individuals
diagnosed cancer in men and the second leading diagnosed with high-risk PCa are typically treated with
cause of death . Androgens, which regulate normal surgery or a combination of radiation and androgen
[1]
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