Receptors for androgen-binding proteins: Internalization and intracellular signalling

doi:10.1016/0960-0760(95)00111-C

The Journal of Steroid Biochemistry and Molecular Biology

Volume 53, Issues 1–6, June 1995, Pages 561-565

https://doi.org/10.1016/0960-0760(95)00111-C Get rights and content

Abstract

In plasma, most steroid hormones are bound and transported by the specific binding protein, testosterone-estradiol-binding globulin (TeBG). For years, it was believed that the only function of this protein was to regulate the concentration of free steroids in plasma. However, a number of reports have provided evidence for the presence of specific TeBG receptors on plasma membranes. Furthermore, the interaction of TeBG with its receptor was shown to be inhibited when steroids are bound to TeBG, suggesting that TeBG is an allosteric protein. The purpose of this manuscript is to review the evidence that androgen-binding proteins bind to membrane receptors, and, in some cells, this binding stimulates cAMP accumulation, and transfer $TeBG ABP$ into tissue as a consequence of receptor mediated endocytosis. Recent studies from our laboratories have demonstrated binding and uptake of TeBG by MCF-7 breast cancer cells. The interaction of unligated rabbit TeBG with membranes from MCF-7 cells resulted in a time and concentration-dependent increase in adenylate cyclase activity. The TeBG alone also had a reproducible effect on intact cells by increasing cAMP accumulation by 30–35%. The addition of DHT to cells, after TeBG has been allowed to bind, resulted in increases in cAMP of greater than 4-fold. This effect was not blocked by antiandrogens. These data support the hypothesis that extracellular SHBG is a regulator of cellular function through a membrane receptor that is coupled to adenylate cyclase.

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T, DHEAS, or estrogens are known to bind with cell membrane-bound, G-protein coupled receptors including Gnα11, ZIP9, and GPER-1 to augment non-classical or non-genotropic functions of the steroids (Shihan et al., 2014; Bulldan et al., 2016; Shihan et al., 2013; Carmeci et al., 1997; Funakoshi et al., 2006; Shihan et al., 2015). Membrane receptor-mediated endocytosis also may be involved in the internalization of sex steroids, although the role of endocytosis in nuclear receptor-mediated functions of the steroids is not clear (Lin and Scanlan, 2005; Hammes et al., 2005; Porto et al., 1995). The organic solute and steroid transporter (OST) proteins OSTα-OSTβ was proposed to be a newly identified putative steroid transporter (Ballatori, 2005).
Steroid hormones play important roles in normal physiological functions and diseases. Sex steroids hormones are important in the biology and treatment of sex hormone-related cancer such as prostate cancer and breast cancer. Cells may take up steroids using multiple mechanisms. The conventionally accepted hypothesis that steroids cross cell membrane through passive diffusion has not been tested rigorously. Experimental data suggested that cells may take up sex steroid using an active uptake mechanism. ³H-testosterone uptake by prostate cancer cells showed typical transporter-mediated uptake kinetic. Cells retained testosterone taken up from the medium. The uptake of testosterone was selective for certain steroid hormones but not others. Data also indicated that the active and selective uptake mechanism resided in cholesterol-rich membrane domains, and may involve ATP and membrane transporters. In summary, the present study provided strong evidence to support the existence of an active and selective molecular mechanism for sex steroid uptake.
The low dose gamma ionising radiation impact upon cooperativity of androgen-specific proteins
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The functions of TeBG include not only transport of androgens (A) and their clearance. Also the ‘active conformation’ of TeBG acts as an activator for adenylate cyclase or PM-G-proteins (nongenomic signaling) and as a transmitter of T to the AR on PM (Larriva-Sahd et al., 1991; Konoplya and Popoff, 1992; Porto et al., 1995; Rosner et al., 1999). Polyacrylamide gel electrophoresis of serum samples under non-denaturing conditions (decreased temperature, mild separation without sodium dodecyl sulfate and β-mercaptoethanol) revealed the concurrent presence: 1) of rTeGB as oligo- (212 kDa), di- (106 kDa) and monomers (53 kDa); also 2) of hTeGB as oligo- (188 ÷ 214 kDa), di- (94 ÷ 107 kDa) and monomers (53.4- and 46 kDa).
The paper deals with effects of the ionising radiation (γ-IR, 0.5 Gy) upon serum testosterone (T), characteristics of testosterone-binding globulin (TeBG) and androgen receptor (AR) in parallel with observation of androgen (A) responsive enzyme activity – hexokinase (HK). The interdependence or relationships of T-levels with parameters of the proteins that provide androgenic regulation are consequently analyzed in post-IR dynamics. The IR-stress adjustment data reveal expediency of TeBG- and AR-cooperativity measurements for more precise assessments of endocrine A-control at appropriate emergencies.
Relation of total and free testosterone and sex hormone-binding globulin with cardiovascular risk factors in men aged 24-45 years. The Cardiovascular Risk in Young Finns Study
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Total and free testosterone decrease gradually in men with advancing age but it is not completely known how lower levels of testosterone are related with various cardiovascular risk factors. We studied the levels of total testosterone, calculated free testosterone and sex hormone-binding globulin (SHBG), and their relations with cardiovascular risk factors in young Finnish men.
The study cohort consisted of 24–45-year-old men participating the Cardiovascular Risk in Young Finns Study in the follow-up surveys performed in 2001 (N = 1024) and 2007 (N = 991). Levels of total testosterone, SHBG, lipids, glucose, insulin, blood pressure and anthropometric factors were measured and free testosterone was calculated.
In multivariable analyses adjusted for age, body mass index and life-style factors (alcohol consumption, smoking and physical activity), total and calculated free testosterone were inversely correlated with triglycerides (both P < 0.0001), insulin (P = 0.0004 and P = 0.01), systolic blood pressure (P = 0.007 and P = 0.01), and directly with high-density lipoprotein (HDL) cholesterol (P < 0.0001 and P = 0.003). SHBG was inversely correlated with triglycerides and insulin, and directly with HDL-cholesterol (all P < 0.001). In longitudinal analyses, lower levels of testosterone and SHBG were associated with higher levels of triglycerides and insulin six years later (all P < 0.01). Baseline level of SHBG was directly associated with HDL-cholesterol (P < 0.0001).
In young and middle-aged men, higher levels of testosterone and SHBG are associated with favourable cardiovascular risk profile characterized by lower levels of triglycerides, insulin and systolic blood pressure, and higher levels of HDL-cholesterol.
Low serum sex hormone-binding globulin: Marker of inflammation?
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Citation Excerpt :
Sex hormone-binding globulin (SHBG), the binding globulin of sex hormones, can regulate the levels of free sex hormones and has been found to be biologically active recently [2]. In other words, SHBG may exert biological functions through itself and regulation of the levels of free sex hormones [3]. In human studies, serum SHBG was negatively correlated with obesity [4], dyslipidemia [5], metabolic syndrome (MetS) [6], insulin resistance [7], and type 2 diabetes [8].
Low sex hormone-binding globulin (SHBG) is associated with metabolic syndrome (MetS), but its relationship with inflammation is unclear.
This cross-sectional study included 696 subjects (255 men, 235 pre-menopausal women, and 206 postmenopausal women). Body mass index, waist circumference, blood pressure, lipid profiles, plasma glucose, insulin, FSH, LH, total testosterone (TT), estradiol, SHBG, dehydroepiandrosterone sulfate (DHEA-S), and hs-CRP concentrations were measured. MetS was defined according to the updated National Cholesterol Education Program criteria with modification of waist circumference for Asians.
Serum hs-CRP and SHBG were negatively correlated in men (r = − 0.29, p < 0.001), pre-menopausal women (r = − 0.38, p < 0.001), and postmenopausal women (r = − 0.27, p < 0.001). In men, TT and hs-CRP showed a negative association (r = − 0.25, p < 0.001), but the association was attenuated after adjusting for SHBG (r = − 0.14, p = 0.039). Multivariate regression models showed that SHBG was independently associated with hs-CRP in men (r = − 0.18, p = 0.009), pre-menopausal women (r = − 0.15, p = 0.025), and postmenopausal women (r = − 0.21, p = 0.005), adjusted for age, MetS components, insulin resistance, low-density lipoprotein-cholesterol, and serum sex hormone levels.
Serum SHBG and hs-CRP concentrations were inversely correlated in men, pre-menoposal, and post-menopausal women independently.
Sex hormone-binding globulin and type 2 diabetes mellitus
2012, Trends in Endocrinology and Metabolism
Sex hormone-binding globulin (SHBG) has emerged as one of the multiple genetic and environmental factors that potentially contribute to the pathophysiology of type 2 diabetes mellitus (T2DM). In addition to epidemiologic studies demonstrating a consistent relationship between decreased levels of serum SHBG and incident T2DM, recent genetic studies also reveal that transmission of specific polymorphisms in the SHBG gene influence the risk of T2DM. At the molecular level, the multiple interactions between SHBG and its receptors in various target tissues suggest physiologic roles for SHBG that are more complex than the simple transport of sex hormones in serum. Taken together, these data provide support for an expanded role of SHBG in the pathophysiology of insulin resistance and T2DM.
(Arene)Cl<inf>2</inf>Ru(II) complexes with N-coordinated estrogen and androgen isonicotinates: Interaction with sex hormone binding globulin and anticancer activity
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(Arene)dichloridoruthenium(II) complexes with N-coordinated isonicotinates of androgens (6) and estrogens (9) were prepared and tested for affinity to the estrogen receptor (ERα) and sex hormone binding globulin (SHBG), as well as for cytotoxicity in cancer cells. None of the new complexes bound noticeably to the ER and most of them also bound less strongly to SHBG than the corresponding unmetallated steroids 7. In MTT assays the Ru(p-cymene) complexes 9 of 2-substituted estrones were equally or even more cytotoxic than the metal-free steroids against hormone-dependent (MCF-7 breast and KB-V1 cervix carcinomas) and hormone-independent (518A2 melanoma) cells. The addition of external SHBG to MTT assays lowered the cytotoxicities of the complexes 9 and distinctly more so those of some steroids 7, probably by the way of sequestration and reduction of the cellular uptake. In the absence of SHBG the estrogen complexes 9 were internalized by 518A2 melanoma cells and ruthenated their DNA as quantified by ICP-OES. They also ruthenated salmon sperm DNA but did not change the topology of plasmid DNA in EMSA experiments. In addition, the Ru(p-cymene) complex of 2-ethoxyestrone (9c) was shown to reduce the motility of 518A2 melanoma cells in a wound-healing assay.

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Receptors for androgen-binding proteins: Internalization and intracellular signalling

Abstract

J. Biol. Chem.

J. Steroid. Biochem.

J. Biol. Chem.

J. Steroid Biochem.

J. Biol. Chem.

Molec. Cell. Endocr.

Steroids

The human sex hormone-binding globulin contains exons for androgen-binding protein and two other testicular messenger RNAs

Molec. Endocr.

Characterization of the human sex hormone binding globulin (SHBG) gene and demonstration of two transcripts in both liver and testis

Nucl. Acids Res.

Human testosterone-binding globulin is a dimer composed of two identical protomers that are differentially glycosylated

Endocrinology

Influence of purified plasma proteins on testosterone uptake and metabolism by normal and hyperplastic human prostate in constant-flow organ culture

J. Clin. Endocr. Metab.

Androgen-binding proteins in human benign prostatic hypertrophy

J. Clin. Endocr. Metab.

The functions of corticosteroid-binding globulin and sex hormone-binding globulin: recent advances

Endocrine Rev.

Evidence that extracellular androgen binding-proteins are signal transducers

Receptor-mediated endocytosis of an extracellular steroid-binding protein (TeBG) in MCF-7 human breast cancer cells

Endocrinology

Binding of an extracellular steroid-binding globulin to membranes and soluble receptors from human breast cancer cells (MCF-7 cells)

Endocrinology