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Sex Hormone Binding Globulin Modifies Testosterone Action and Metabolism in Prostate Cancer Cells.

ABSTRACT: Sex Hormone Binding Globulin (SHBG) is the major serum carrier of sex hormones. However, growing evidence suggests that SHBG is internalised and plays a role in regulating intracellular hormone action. This study was to determine whether SHBG plays a role in testosterone uptake, metabolism, and action in the androgen sensitive LNCaP prostate cancer cell line. Internalisation of SHBG and testosterone, the effects of SHBG on testosterone uptake, metabolism, regulation of androgen responsive genes, and cell growth were assessed. LNCaP cells internalised SHBG by a testosterone independent process. Testosterone was rapidly taken up and effluxed as testosterone-glucuronide; however this effect was reduced by the presence of SHBG. Addition of SHBG, rather than reducing testosterone bioavailability, further increased testosterone-induced expression of prostate specific antigen and enhanced testosterone-induced reduction of androgen receptor mRNA expression. Following 38 hours of testosterone treatment cell morphology changed and growth declined; however, cotreatment with SHBG abrogated these inhibitory effects. These findings clearly demonstrate that internalised SHBG plays an important regulatory and intracellular role in modifying testosterone action and this has important implications for the role of SHBG in health and disease.

SUBMITTER: Li H

PROVIDER: S-EPMC5136390 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Sex Hormone Binding Globulin Modifies Testosterone Action and Metabolism in Prostate Cancer Cells.

Li Huika H Pham Thy T McWhinney Brett C BC Ungerer Jacobus P JP Pretorius Carel J CJ Richard Derek J DJ Mortimer Robin H RH d'Emden Michael C MC Richard Kerry K

International journal of endocrinology 20161120

Sex Hormone Binding Globulin (SHBG) is the major serum carrier of sex hormones. However, growing evidence suggests that SHBG is internalised and plays a role in regulating intracellular hormone action. This study was to determine whether SHBG plays a role in testosterone uptake, metabolism, and action in the androgen sensitive LNCaP prostate cancer cell line. Internalisation of SHBG and testosterone, the effects of SHBG on testosterone uptake, metabolism, regulation of androgen responsive genes, ...[more]

PMID: 27990161

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Project description:ContextTestosterone (T) is a central androgenic hormone, and sex hormone-binding globulin (SHBG) is the major determinant of its bioactivity. There are no acknowledged genetic variants with clear-cut clinical implications, modulating T levels in men.ObjectiveTo confirm genetic associations of top loci (SHBG, GCKR, SLCO1B1, and JMJD1C) from genome-wide association (GWA) studies for serum SHBG and T.Design patientsGroups differing in general and reproductive parameters: young men (n = 540; 19.3 ± 1.8 years), severe idiopathic male infertility patients (n = 641; 31.6 ± 6.0 years), and male partners of pregnant women (n = 324; 31.9 ± 6.6 years). All patients were recruited at the Andrology Centre, Tartu University Hospital, Estonia.Main outcome measuresGenetic associations with reproductive hormones, testicular and sperm parameters (linear regression, additive model); intergroup allele/genotype distribution comparisons.ResultsAssociations with serum SHBG levels were robust for SHBG -68 G>A [rs1799941; meta-analysis: P = 3.7 × 10-14; allelic effect (standard error) = 4.67 (0.62) nmol/L], SHBG +1091 C>T [rs727428; P = 7.3 × 10-11; -3.74 (0.57)], SHBG Pro185Leu [rs6258; P = 1.2 × 10-4, -12.2 (3.17)], and GCKR Pro446Leu [rs1260326; P = 1.5 × 10-4; -2.2 (0.59)]. Measured T concentrations correlated with genetically modulated levels of SHBG (r = 0.48 to 0.74, P < 0.0001), guaranteeing stable availability of free T. Among infertile men, SHBG Pro185Leu substitution showed additional downstream effect on luteinizing hormone [P = 5.1 × 10-5; -1.66 (0.57) IU/L] and follicle-stimulating hormone [P = 3.4 × 10-3; -2.48 (1.23) IU/L]. No associations with male reproductive parameters were detected for SHBG Asp327Asn (rs6259), SLCO1B1 Val174Ala (rs4149056), and JMJD1C intronic variant rs7910927.ConclusionsClaims were replicated and additional associations were detected for four of seven tested GWAS top loci. Perspective clinical investigations of these variants are hypotestosteronemia among aging men and pharmacogenetics of hormone replacement therapy.

Dataset Information

Sex Hormone Binding Globulin Modifies Testosterone Action and Metabolism in Prostate Cancer Cells.

Publications

Sex Hormone Binding Globulin Modifies Testosterone Action and Metabolism in Prostate Cancer Cells.

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