Androgen-metabolizing enzymes: A structural perspective

Manenda, Mahder Seifu; Hamel, Charles Jérémie; Masselot--Joubert, Loreleï; Picard, Marie-Ève; Shi, Rong

doi:10.1016/j.jsbmb.2016.02.021

Cited by 9 publications

(6 citation statements)

References 125 publications

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“… 1 Luu-The and Labrie ( 2010 ), Labrie and Labrie ( 2013 ), and Labrie ( 2015 ); 2 Smuc and Rizner ( 2009 ), 3 Miller et al ( 2012b ), 4 Sivik ( 2012 ); 5 GeneCards ( www.genecards.org . Accessed on date: February, 2018) Stelzer et al ( 2016 ), 6 Smuc and Rizner ( 2009 ), 7 Penning et al ( 2004 ), Steckelbroeck et al ( 2010 ); 8 Jin et al ( 2011 ), 9 Manenda et al ( 2016 ), 10 Balk and Knudsen ( 2008 ), 11 Gangloff et al ( 2003 ), 12 Bélanger et al ( 2002 ), 13 Perez Carrion et al ( 1994 ), 14 Möller et al ( 1999 ), Moeller and Adamski ( 2009 ), 15 Cornel et al ( 2017 ), 16 Sinreih et al ( 2017b ), 17 Casey et al ( 1994 ), 18 Törn et al ( 2003 ), 19 Ohno et al ( 2008 ), 20 Yang et al ( 2016 ), 21 Chai et al ( 2003 ), 22 Sakurai et al ( 2006 ), 23 Endo et al ( 2016 ). 24 Rižner and Penning ( 2014 ), 25 Manenda et al ( 2016 ), 26 Lin et al ( 1997 ), 27 Miki et al ( 2002 ), 28 Foster et al ( 2008a ), 29 Purohit and Foster ( 2012 ), 30 Mueller et al ( 2015 ), 31 Marchais-Oberwinkler et al ( 2011 ), Mueller et al ( 2015 ), 32 Rege et al ( 2016 ), 33 Strott ( 2002 ), and 34 Yang et al ( <...>…”

Section: From Ovarian Estrogen Synthesis To Intracrinologymentioning

confidence: 99%

Intracrine Regulation of Estrogen and Other Sex Steroid Levels in Endometrium and Non-gynecological Tissues; Pathology, Physiology, and Drug Discovery

et al. 2018

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Our understanding of the intracrine (or local) regulation of estrogen and other steroid synthesis and degradation expanded in the last decades, also thanks to recent technological advances in chromatography mass-spectrometry. Estrogen responsive tissues and organs are not passive receivers of the pool of steroids present in the blood but they can actively modify the intra-tissue steroid concentrations. This allows fine-tuning the exposure of responsive tissues and organs to estrogens and other steroids in order to best respond to the physiological needs of each specific organ. Deviations in such intracrine control can lead to unbalanced steroid hormone exposure and disturbances. Through a systematic bibliographic search on the expression of the intracrine enzymes in various tissues, this review gives an up-to-date view of the intracrine estrogen metabolisms, and to a lesser extent that of progestogens and androgens, in the lower female genital tract, including the physiological control of endometrial functions, receptivity, menopausal status and related pathological conditions. An overview of the intracrine regulation in extra gynecological tissues such as the lungs, gastrointestinal tract, brain, colon and bone is given. Current therapeutic approaches aimed at interfering with these metabolisms and future perspectives are discussed.

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Section: From Ovarian Estrogen Synthesis To Intracrinologymentioning

confidence: 99%

Intracrine Regulation of Estrogen and Other Sex Steroid Levels in Endometrium and Non-gynecological Tissues; Pathology, Physiology, and Drug Discovery

et al. 2018

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“…It has been demonstrated that the abnormal function of the androgen metabolic pathway plays key role in the occurrence of CRPC [29]. The androgen metabolic pathway consists of several components, which include cytochromes P450 (CYPs) [30].CYPs are one of the largest and most diverse superfamily of enzymes [6]. CYPs are involved in the process of metabolizing various substances.…”

Section: Discussionmentioning

confidence: 99%

CYP19A1 Is Regulated by BRD4 and Suppresses Castration-resistant Prostate Cancer Cell Invasion and Proliferation by Decreasing AR Expression

Chen

Wang

et al. 2022

Preprint

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BackgroundCastration-resistant prostate cancer (CRPC) is the final stage of prostate cancer (PCa). Thus far, there is no effective method for CRPC treatment. Androgen and androgen receptor (AR) play a vital role in CRPC occurrence and drug tolerance. Testosterone is the main androgen in males. CYP19A1 can encode aromatase, a key enzyme that can catalyze the conversion of testosterone to estrogen, and may affect both androgen and AR. CYP19A1 may play a role in the occurrence of CRPC; however, the function of CYP19A1 in CRPC remain unclear.MethodsUsing data from public databases and clinical samples, we analyzed the expression of CYP19A1 in PCa and CRPC specimens. In addition, the influence of CYP19A1 on cell invasion and proliferation was detected in vivo and vitro. The affect of BRD4 on CYP19A1 and AR was detected by qRT-PCR and western blot experiments.ResultsWe found that CYP19A1 was downregulated in CRPC samples and cells. CYP19A1 overexpression decreased CRPC cell invasion and proliferation. In addition, CYP19A1 expression was negatively correlated with AR expression. CYP19A1 affected CRPC cell invasion and proliferation ability by suppressing the expression of AR, and this may be attributed to the metabolism of testosterone by CYP19A1. Moreover, the BRD4 inhibitor-JQ1 induced the expression of CYP19A1 and suppressed the expression of AR. Following BRD4 knockdown, CYP19A1 showed a higher expression level, and, AR expression was decreased. ConclusionsIn conclusion, our findings demonstrated that CYP19A1 could reduce CRPC cell invasion and proliferation by targeting AR, and this process could be regulated by BRD4. The BRD4-CYP19A1-AR pathway may be a potential cause of CRPC occurrence. Therefore, CYP19A1 may be a potential therapeutic target for treating CRPC.

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“…To date, there are eight co-crystal structures of CYP17A1 complexed with an inhibitor or substrate and revealing the characteristic cytochrome P450 fold [31] . The crystal structure of CYP17A1 bound either to abiraterone [ Figure 3A] or to galeterone (TOK-001), two clinically trailed CYP17A1 inhibitors (2 and 3, Figure 4), show that both inhibitors bind the haem iron at a 60° angle above the haeme plane while aligning their chemical structures against the central helix with the 3β-OH interacting with Asn 202 in the F helix [32] .…”

Section: Cyp17a1mentioning

confidence: 99%

Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

Pippione¹,

Boschi²,

Pors³

et al. 2017

JCMT

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Androgens play an important role in prostate cancer (PCa) development and progression. Although androgen deprivation therapy remains the front-line treatment for advanced prostate cancer, patients eventually relapse with the lethal form of the disease. The prostate tumor microenvironment is characterised by elevated tissue androgens that are capable of activating the androgen receptor (AR). Inhibiting the steroidogenic enzymes that play vital 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 pre-receptor control of T and DHT biosynthesis by alternative pathways in controlling intratumoral androgen levels, and thereby influencing PCa progression. This supports the idea for the development of multi-targeting strategies, involving both dual and multiple inhibitors of androgen-metabolising enzymes that are able to affect androgen synthesis and signalling at different points in the biosynthesis. In this review, we will focus on CYP17A1, AKR1C3, HSD17B3 and SRD5A, as these enzymes play essential roles in all the three androgenic pathways. We will review also the AR as an additional target for the design of bifunctional drugs. Targeting intracrine androgens and AKR1C3 have potential to overcome enzalutamide and abiraterone resistance and improve survival of advanced prostate cancer patients.

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Androgen-metabolizing enzymes: A structural perspective

Cited by 9 publications

References 125 publications

Intracrine Regulation of Estrogen and Other Sex Steroid Levels in Endometrium and Non-gynecological Tissues; Pathology, Physiology, and Drug Discovery

Intracrine Regulation of Estrogen and Other Sex Steroid Levels in Endometrium and Non-gynecological Tissues; Pathology, Physiology, and Drug Discovery

CYP19A1 Is Regulated by BRD4 and Suppresses Castration-resistant Prostate Cancer Cell Invasion and Proliferation by Decreasing AR Expression

Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

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