Dataset Information

Consecutive Prostate Cancer Specimens Revealed Increased Aldo?Keto Reductase Family 1 Member C3 Expression with Progression to Castration-Resistant Prostate Cancer.

ABSTRACT: Aldo-keto reductase family 1 member C3 (AKR1C3) is an enzyme in the steroidogenesis pathway, especially in formation of testosterone and dihydrotestosterone, and is believed to have a key role in promoting prostate cancer (PCa) progression, particularly in castration-resistant prostate cancer (CRPC). This study aims to compare the expression level of AKR1C3 between benign prostatic epithelium and cancer cells, and among hormone-naïve prostate cancer (HNPC) and CRPC from the same patients, to understand the role of AKR1C3 in PCa progression. Correlation of AKR1C3 immunohistochemical expression between benign and cancerous epithelia in 134 patient specimens was analyzed. Additionally, correlation between AKR1C3 expression and prostate-specific antigen (PSA) progression-free survival (PFS) after radical prostatectomy was analyzed. Furthermore, we evaluated the consecutive prostate samples derived from 11 patients both in the hormone-naïve and castration-resistant states. AKR1C3 immunostaining of cancer epithelium was significantly stronger than that of the benign epithelia in patients with localized HNPC (p < 0.0001). High AKR1C3 expression was an independent factor of poor PSA PFS (p = 0.032). Moreover, AKR1C3 immunostaining was significantly stronger in CRPC tissues than in HNPC tissues in the same patients (p = 0.0234). Our findings demonstrate that AKR1C3 is crucial in PCa progression.

SUBMITTER: Miyazaki Y

PROVIDER: S-EPMC6571723 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Consecutive Prostate Cancer Specimens Revealed Increased Aldo⁻Keto Reductase Family 1 Member C3 Expression with Progression to Castration-Resistant Prostate Cancer.

Miyazaki Yu Y Teramoto Yuki Y Shibuya Shinsuke S Goto Takayuki T Okasho Kosuke K Mizuno Kei K Uegaki Masayuki M Yoshikawa Takeshi T Akamatsu Shusuke S Kobayashi Takashi T Ogawa Osamu O Inoue Takahiro T

Journal of clinical medicine 20190501 5

Aldo-keto reductase family 1 member C3 (AKR1C3) is an enzyme in the steroidogenesis pathway, especially in formation of testosterone and dihydrotestosterone, and is believed to have a key role in promoting prostate cancer (PCa) progression, particularly in castration-resistant prostate cancer (CRPC). This study aims to compare the expression level of AKR1C3 between benign prostatic epithelium and cancer cells, and among hormone-naïve prostate cancer (HNPC) and CRPC from the same patients, to und ...[more]

PMID: 31052459

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Project description:The progression of castration resistant prostate cancer (CRPC) is driven by the intratumoral conversion of adrenal androgen precursors to potent androgens. The expression of aldo-keto reductase 1C3 (AKR1C3), which catalyses the reduction of weak androgens to more potent androgens, is significantly increased in CRPC tumours. The oxidation of androgens to their inactive form is catalysed by 17β-hydroxysteroid dehydrogenase type 2 (17βHSD2), but little attention is given to the expression levels of this enzyme. In this study, we show that the 11-oxygenated androgen precursors of adrenal origin are the preferred substrate for AKR1C3. In particular we show that the enzymatic efficiency of AKR1C3 is 8- and 24-fold greater for 11-ketoandrostenedione than for the classic substrates androstenedione and 5α-androstanedione, respectively. Using three independent experimental systems and a computational model we subsequently show that increased ratios of AKR1C3:17βHSD2 significantly favours the flux through the 11-oxygenated androgen pathway as compared to the classical or 5α-androstanedione pathways. Our findings reveal that the flux through the classical and 5α-androstanedione pathways are limited by the low catalytic efficiently of AKR1C3 towards classical androgens combined with the high catalytic efficiency of 17βHSD2, and that the expression of the oxidative enzyme therefore plays a vital role in determining the steady state concentration of active androgens. Using microarray data from prostate tissue we confirm that the AKR1C3:17βHSD2 ratio is significantly increased in patients undergoing androgen deprivation therapy as compared to benign tissue, and further increased in patients with CRPC. Taken together this study therefore demonstrates that the ratio of AKR1C3:17βHSD2 is more important than AKR1C3 expression alone in determining intratumoral androgen levels and that 11-oxygenated androgens may play a bigger role in CRPC than previously anticipated.

Project description:SULT2B1b (SULT2B) is a prostate-expressed hydroxysteroid sulfotransferase, which may regulate intracrine androgen homeostasis by mediating 3β-sulfation of dehydroepiandrosterone (DHEA), the precursor for 5α-dihydrotestosterone (DHT) biosynthesis. The aldo-keto reductase (AKR)1C3 regulates androgen receptor (AR) activity in castration-resistant prostate cancer (CRPC) by promoting tumor tissue androgen biosynthesis from adrenal DHEA and also by functioning as an AR-selective coactivator. Herein we report that SULT2B-depleted CRPC cells, arising from stable RNA interference or gene knockout (KO), are markedly upregulated for AKR1C3, activated for ERK1/2 survival signal, and induced for epithelial-to-mesenchymal (EMT)-like changes. EMT was evident from increased mesenchymal proteins and elevated EMT-inducing transcription factors SNAI1 and TWIST1 in immunoblot and single-cell mass cytometry analyses. SULT2B KO cells showed greater motility and invasion in vitro; growth escalation in xenograft study; and enhanced metastatic potential predicted on the basis of decreased cell stiffness and adhesion revealed from atomic force microscopy analysis. While AR and androgen levels were unchanged, AR activity was elevated, since PSA and FKBP5 mRNA induction by DHT-activated AR was several-fold higher in SULT2B-silenced cells. AKR1C3 silencing prevented ERK1/2 activation and SNAI1 induction in SULT2B-depleted cells. SULT2B was undetectable in nearly all CRPC metastases from 50 autopsy cases. Primary tumors showed variable and Gleason score (GS)-independent SULT2B levels. CRPC metastases lacking SULT2B expressed AKR1C3. Since AKR1C3 is frequently elevated in advanced prostate cancer, the inhibitory influence of SULT2B on AKR1C3 upregulation, ERK1/2 activation, EMT-like induction, and on cell motility and invasiveness may be clinically significant. Pathways regulating the inhibitory SULT2B-AKR1C3 axis may inform new avenue(s) for targeting SULT2B-deficient prostate cancer.

Project description:BackgroundAndrogen deprivation therapy (ADT) is an effective palliation treatment in men with advanced prostate cancer (PC). However, ADT has well documented side effects that could alter the patient's health-related quality of life (HRQoL). The current study aims to test whether a genetic stratification could provide better knowledge for optimising ADT options to minimize HRQoL effects.MethodsA cohort of 206 PC survivors (75 treated with and 131 without ADT) was recruited with written consent to collect patient characteristics, clinical data and HRQoL data related to PC management. The primary outcomes were the percentage scores under each HRQoL subscale assessed using the European Organisation for Research and Treatment of Cancer Quality of Life questionnaires (QLQ-C30 and PR25) and the Depression Anxiety Stress Scales developed by the University of Melbourne, Australia. Genotyping of these men was carried out for the aldo-keto reductase family 1, member C3 (AKR1C3) rs12529 single nucleotide polymorphism (SNP). Analysis of HRQoL scores were carried out against ADT duration and in association with the AKR1C3 rs12529 SNP using the generalised linear model. P-values <0 · 05 were considered significant, and were further tested for restriction with Bonferroni correction.ResultsIncrease in hormone treatment-related effects were recorded with long-term ADT compared to no ADT. The C and G allele frequencies of the AKR1C3rs12529 SNP were 53·4 % and 46·6 % respectively. Hormone treatment-related symptoms showed an increase with ADT when associated with the AKR1C3 rs12529 G allele. Meanwhile, decreasing trends on cancer-specific symptoms and increased sexual interest were recorded with no ADT when associated with the AKR1C3 rs12529 G allele and reverse trends with the C allele. As higher incidence of cancer-specific symptoms relate to cancer retention it is possible that associated with the C allele there could be higher incidence of unresolved cancers under no ADT options.ConclusionsIf these findings can be reproduced in larger homogeneous cohorts, a genetic stratification based on the AKR1C3 rs12529 SNP, can minimize ADT-related HRQoL effects in PC patients. Our data additionally show that with this stratification it could also be possible to identify men needing ADT for better oncological advantage.

Project description:Aldo-keto reductases (AKRs) are phase I metabolising enzymes that catalyse the reduced nicotinamide adenine dinucleotide (phosphate) (NAD(P)H)-dependent reduction of carbonyl groups to yield primary and secondary alcohols on a wide range of substrates, including aliphatic and aromatic aldehydes and ketones, ketoprostaglandins, ketosteroids and xenobiotics. In so doing they functionalise the carbonyl group for conjugation (phase II enzyme reactions). Although functionally diverse, AKRs form a protein superfamily based on their high sequence identity and common protein fold, the (alpha/beta) 8 -barrel structure. Well over 150 AKR enzymes, from diverse organisms, have been annotated so far and given systematic names according to a nomenclature that is based on multiple protein sequence alignment and degree of identity. Annotation of non-vertebrate AKRs at the National Center for Biotechnology Information or Vertebrate Genome Annotation (vega) database does not often include the systematic nomenclature name, so the most comprehensive overview of all annotated AKRs is found on the AKR website (http://www.med.upenn.edu/akr/). This site also hosts links to more detailed and specialised information (eg on crystal structures, gene expression and single nucleotide polymorphisms [SNPs]). The protein-based AKR nomenclature allows unambiguous identification of a given enzyme but does not reflect the wealth of genomic and transcriptomic variation that exists in the various databases. In this context, identification of putative new AKRs and their distinction from pseudogenes are challenging. This review provides a short summary of the characteristic features of AKR biochemistry and structure that have been reviewed in great detail elsewhere, and focuses mainly on nomenclature and database entries of human AKRs that so far have not been subject to systematic annotation. Recent developments in the annotation of SNP and transcript variance in AKRs are also summarised.

Dataset Information

Consecutive Prostate Cancer Specimens Revealed Increased Aldo?Keto Reductase Family 1 Member C3 Expression with Progression to Castration-Resistant Prostate Cancer.

Publications

Consecutive Prostate Cancer Specimens Revealed Increased Aldo⁻Keto Reductase Family 1 Member C3 Expression with Progression to Castration-Resistant Prostate Cancer.

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