Multiple roles for udp-glucuronosyltransferase (UGT)2B15 and UGT2B17 enzymes in androgen metabolism and prostate cancer evolution

Gauthier-Landry, Louis; Bélanger, Alain; Barbier, Olivier

doi:10.1016/j.jsbmb.2014.05.009

Cited by 51 publications

(35 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…UGTrelated pathways play an important role in androgens metabolism [114,115], and MS analysis demonstrated reduced levels of glucuronic acid in CRPC cells, indicating an increased use for the glucuronidation reactions involved in androstane-3a,17b-diol-G glucuronides synthesis. Supporting these findings, previous studies had shown a higher expression of UGT2B15 and UGT2B17 in CRPC cells [116,117]. Therefore, to evaluate the prognostic value of the UGT-associated pathways, Kaushik et al [113] examined three independent gene expression datasets and investigated whether UGT2B15, UGT2A1, and UGT2B28 (three genes associated with UGT activity) had any correlation with PCa biochemical recurrence.…”

mentioning

confidence: 80%

Metabolomic profiling for the identification of novel diagnostic markers in prostate cancer

Lucarelli

Rutigliano

Galleggiante

et al. 2015

Expert Review of Molecular Diagnostics

View full text Add to dashboard Cite

Metabolomic profiling offers a powerful methodology for understanding the perturbations of biochemical systems occurring during a disease process. During neoplastic transformation, prostate cells undergo metabolic reprogramming to satisfy the demands of growth and proliferation. An early event in prostate cell transformation is the loss of capacity to accumulate zinc. This change is associated with a higher energy efficiency and increased lipid biosynthesis for cellular proliferation, membrane formation and cell signaling. Moreover, recent studies have shown that sarcosine, an N-methyl derivative of glycine, was significantly increased during disease progression from normal to localized to metastatic prostate cancer. Mapping the metabolomic profiles to their respective biochemical pathways showed an upregulation of androgen-induced protein synthesis, an increased amino acid metabolism and a perturbation of nitrogen breakdown pathways, along with high total choline-containing compounds and phosphocholine levels. In this review, the role of emerging biomarkers is summarized, based on the current understanding of the prostate cancer metabolome.

show abstract

mentioning

confidence: 80%

Metabolomic profiling for the identification of novel diagnostic markers in prostate cancer

Lucarelli

Rutigliano

Galleggiante

et al. 2015

Expert Review of Molecular Diagnostics

View full text Add to dashboard Cite

show abstract

“…A nonsynonymous single nucleotide polymorphism (SNP) in UGT2B15 (D85Y, rs1902923: G>T) increases maximal velocity for DHT and androstanediol 2-fold and occurs in 32% of Caucasians [64]. CNV in UBT2B17 and UGT2B28 are associated with decreased levels of circulating androgen-glucuronides, while CNV in UGT2B17 are also associated with altered levels of intraprostatic and urinary androgen-glucuronides [65–67]. …”

Section: Genetic Variation In Genes Involved In Pre-receptor Contrmentioning

confidence: 99%

“…Gene deletions in UGT2B17 have been linked with an increased risk of biochemical relapse, while deletion of UGT2B17 and the UGT2B15 SNP D85Y have been linked with increased PCa risk in some (but not all) studies [67–71]. In particular, the UGT2B17 homozygous deletion polymorphism was associated with: 1) an increased risk of biochemical recurrence after surgical treatment and significantly lower androgen glucuronides in Caucasian and Asian patients [71]; 2) an increased risk for PCa compared with insertion carriers in Caucasian and Swedish individuals, but not in African American men [72–74]; and 3) in two meta-analyses spanning 17,000 subjects, was linked to an increased PCa susceptibility [75, 76].…”

Section: Genetic Variation In Genes Involved In Pre-receptor Contrmentioning

confidence: 99%

“…For example, while UGT genes are generally repressed by AR regulated signaling [47, 67], UGT2B17 has been identified as a positively regulated gene target of the constitutively active AR splice variants present in many CRPC tumors [67]. Thus, its presence in CRPC tumors may simply be a reflection of an altered, AR-variant associated transcriptional profile rather than an inherently pathogenic alteration.…”

Section: A Non-classical Role For Dht Metabolizing Enzymesmentioning

confidence: 99%

See 1 more Smart Citation

Classical and Non-Classical Roles for Pre-Receptor Control of DHT Metabolism in Prostate Cancer Progression

Zhang

Plymate

et al. 2016

HORM CANC

View full text Add to dashboard Cite

Androgens play an important role in prostate cancer (PCa) development and progression. Accordingly, androgen deprivation therapy remains the front-line treatment for locally recurrent or advanced PCa, but patients eventually relapse with the lethal form of the disease termed castration resistant PCa (CRPC). Importantly, castration does not eliminate androgens from the prostate tumor microenvironment which is characterized by elevated tissue androgens that are well within the range capable of activating the androgen receptor (AR). In this mini-review, we discuss emerging data that suggest a role for the enzymes mediating pre-receptor control of dihydrotestosterone (DHT) metabolism, including AKR1C2, HSD17B6, HSD17B10 and the UGT family members UGT2B15 and UGT2B17, in controlling intra-tumoral androgen levels, and thereby influencing PCa progression. We review the expression of steroidogenic enzymes involved in this pathway in primary PCa and CRPC, the activity and regulation of these enzymes in PCa experimental models, and the impact of genetic variation in genes mediating pre-receptor DHT metabolism on PCa risk. Finally, we discuss recent data that suggests several of these enzymes may also play an unrecognized role in CRPC progression separate from their role in androgen inactivation.

show abstract

“…The expression of UGT2B17 in sex hormone-sensitive organs also indicates its role in sex hormone homeostasis. For example, although controversial, gene deletion in UGT2B17 is associated with greater risk of developing androgen-sensitive prostate diseases (Barbier and Belanger, 2008;Paquet et al, 2012;Kpoghomou et al, 2013;Gauthier-Landry et al, 2015). The UGT2B17 gene-deletion allele has been shown to be associated with several other pathophysiological conditions, such as obesity (Zhu et al, 2015), chronic lymphocytic leukemia (Gruber et al, 2013), and endometrial cancer (Hirata et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Hepatic Abundance and Activity of Androgen- and Drug-Metabolizing Enzyme UGT2B17 Are Associated with Genotype, Age, and Sex

et al. 2018

View full text Add to dashboard Cite

The major objective of this study was to investigate the association of genetic and nongenetic factors with variability in protein abundance and in vitro activity of the androgen-metabolizing enzyme UGT2B17 in human liver microsomes ( = 455). UGT2B17 abundance was quantified by liquid chromatography-tandem mass spectrometry proteomics, and enzyme activity was determined by using testosterone and dihydrotestosterone as in vitro probe substrates. Genotyping or gene resequencing and mRNA expression were also evaluated. Multivariate analysis was used to test the association of UGT2B17 copy number variation, single nucleotide polymorphisms (SNPs), age, and sex with its mRNA expression, abundance, and activity. UGT2B17 gene copy number and SNPs (rs7436962, rs9996186, rs28374627, and rs4860305) were associated with gene expression, protein levels, and androgen glucuronidation rates in a gene dose-dependent manner. UGT2B17 protein (mean ± S.D. picomoles per milligram of microsomal protein) is sparsely expressed in children younger than 9 years (0.12 ± 0.24 years) but profoundly increases from age 9 years to adults (∼10-fold) with ∼2.6-fold greater abundance in males than in females (1.2 vs. 0.47). Association of androgen glucuronidation with UGT2B15 abundance was observed only in the low UGT2B17 expressers. These data can be used to predict variability in the metabolism of UGT2B17 substrates. Drug companies should include UGT2B17 in early phenotyping assays during drug discovery to avoid late clinical failures.

show abstract

Multiple roles for udp-glucuronosyltransferase (UGT)2B15 and UGT2B17 enzymes in androgen metabolism and prostate cancer evolution

Cited by 51 publications

References 75 publications

Metabolomic profiling for the identification of novel diagnostic markers in prostate cancer

Metabolomic profiling for the identification of novel diagnostic markers in prostate cancer

Classical and Non-Classical Roles for Pre-Receptor Control of DHT Metabolism in Prostate Cancer Progression

Hepatic Abundance and Activity of Androgen- and Drug-Metabolizing Enzyme UGT2B17 Are Associated with Genotype, Age, and Sex

Contact Info

Product

Resources

About