Tissue control of androgen action: The ups and downs of androgen receptor expression

Hunter, Irene; Hay, Colin W.; Esswein, Bianca; Watt, Kate; McEwan, Iain J.

doi:10.1016/j.mce.2017.08.002

Cited by 40 publications

(23 citation statements)

References 109 publications

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“…The importance of the AR signaling pathway in the male reproductive system has been studied in depth. The promoter for the AR gene lacks a typical TATA box and, in agreement with many TATA-less genes, transcription is driven primarily by binding of the zinc finger transcription factor Specificity Protein 1 (Sp1) to GC box regulatory elements [50]. In human prostate cancer LNCaP cells, inhibition of Sp1 activity results in a strong decrease in the AR protein level [51], showcasing Sp1 relevance in the regulation of AR transcription.…”

Section: Sertoli Cell Maturation During Postnatal Developmentmentioning

confidence: 99%

Importance of the Androgen Receptor Signaling in Gene Transactivation and Transrepression for Pubertal Maturation of the Testis

Edelsztein

Rey

2019

Cells

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Androgens are key for pubertal development of the mammalian testis, a phenomenon that is tightly linked to Sertoli cell maturation. In this review, we discuss how androgen signaling affects Sertoli cell function and morphology by concomitantly inhibiting some processes and promoting others that contribute jointly to the completion of spermatogenesis. We focus on the molecular mechanisms that underlie anti-Müllerian hormone (AMH) inhibition by androgens at puberty, as well as on the role androgens have on Sertoli cell tight junction formation and maintenance and, consequently, on its effect on proper germ cell differentiation and meiotic onset during spermatogenesis.

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Section: Sertoli Cell Maturation During Postnatal Developmentmentioning

confidence: 99%

Importance of the Androgen Receptor Signaling in Gene Transactivation and Transrepression for Pubertal Maturation of the Testis

Edelsztein

Rey

2019

Cells

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“…It is well known that androgens can increase muscle mass and strength, 7,8 but they are not routinely used to treat these disorders because of their unfavourable side effects in cardiovascular, liver, and reproductive tissues. The androgen receptor (AR) is a nuclear receptor that plays a critical role in the function of several organs including the prostate, testis, ovary, skeletal muscle, and bone 9,10 . AR is activated by binding to ligands such as androgens, after which it translocates into the nucleus, where it binds to androgen response elements within the promoters or enhancers of androgen‐responsive genes such as E‐cadherin 11 and fibroblast growth factor 8 12 .…”

Section: Introductionmentioning

confidence: 99%

Polyamine pathway is associated with muscle anabolic effects by androgen receptor ligand

Kanou

Nakamura

Horie

et al. 2020

JCSM Rapid Communications

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Background Muscle wasting is a common condition concomitant with aging. Androgens significantly increase skeletal muscle mass, but the role of the androgen receptor (AR) in skeletal muscle is not well established. TEI‐SARM2, a novel selective androgen receptor modulator (SARM), was developed as a pharmaceutical candidate for the treatment of muscle wasting diseases. Methods The efficacy and specificity of TEI‐SARM2 were analysed in vitro assays, and efficacy was also evaluated in vivo using orchiectomized male rats, rat tail‐suspension, rat and mice cancer‐induced muscle atrophy models, and female cynomolgus monkeys. Male myofibre‐specific AR‐knockout (mARKO) mice were orchiectomized to investigate the role of AR in muscle using TEI‐SARM2. RNA‐seq analysis of bulbocavernosus muscle was performed. The effects of spermidine were evaluated in C2C12 myoblasts. Results Selective, potent anabolic effects of TEI‐SARM2 in muscle were detected in rats and monkeys. TEI‐SARM2 inhibited muscle loss and promoted muscle recovery in a model of muscle disuse and prevented muscle wasting and improved survival rate in cancer models. In vivo and RNA‐seq analyses revealed that AR regulates skeletal muscle mass in myofibres and extra‐myofibres, both directly and indirectly. Among them, polyamine synthesis‐related genes were focused, and spermidine treatment could induce C2C12 cell proliferation. Conclusions TEI‐SARM2 exhibited potent and selective anabolic effects in muscles, as well as tissue specificity in various animal models. The results support that TEI‐SARM2 is a promising drug candidate for muscle wasting diseases. TEI‐SARM2 induced anabolic effects on skeletal muscle via AR in myofibres as well as other androgen target cells.

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“…However, multiple mechanistic studies have found that the observed antiproliferative effects of the PPARγ agonists occur via PPARγ‐independent pathways . Perhaps the most important of these pathways in PCa is the enhancement of proteasomal degradation of Sp1, a transcriptional factor essential for the expression of multiple genes including the AR . Knockdown of Sp1 by siRNA can reduce the mRNA levels of AR and attenuate AR‐dependent gene transcription .…”

Section: Marine Sponge–derived Compoundsmentioning

confidence: 99%

“…Knockdown of Sp1 by siRNA can reduce the mRNA levels of AR and attenuate AR‐dependent gene transcription . Furthermore, Sp1 undergoes nontranscriptional inhibition by activated AR …”

Section: Marine Sponge–derived Compoundsmentioning

confidence: 99%

Molecules targeting the androgen receptor (AR) signaling axis beyond the AR‐Ligand binding domain

Elshan¹,

Rettig

Jung³

2018

Medicinal Research Reviews

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Prostate cancer (PCa) is the second most common cause of cancer-related mortality in men in the United States. The androgen receptor (AR) and the physiological pathways it regulates are central to the initiation and progression of PCa. As a member of the nuclear steroid receptor family, it is a transcription factor with three distinct functional domains (ligand-binding domain [LBD], DNA-binding domain [DBD], and transactivation domain [TAD]) in its structure. All clinically approved drugs for PCa ultimately target the AR-LBD. Clinically active drugs that target the DBD and TAD have not yet been developed due to multiple factors. Despite these limitations, the last several years have seen a rise in the discovery of molecules that could successfully target these domains. This review aims to present and comprehensively discuss such molecules that affect AR signaling through direct or indirect interactions with the AR-TAD or the DBD. The compounds discussed here include hairpin polyamides, niclosamide, marine sponge-derived small molecules (eg, EPI compounds), mahanine, VPC compounds, JN compounds, and bromodomain and extraterminal domain inhibitors. We highlight the significant in vitro and in Med Res Rev. 2019;39:910-960. wileyonlinelibrary.com/journal/med 910 | -binding domain; LRP6, low-density lipoprotein receptor-related protein 6;MAPK, mitogen-activated protein kinase; mCRPC, metastatic castration-resistant prostate cancer; mTOR, mammalian target of rapamycin; NHR, nuclear hormone receptor; PARP, poly (ADP-ribose) polymerase; PCa, prostate cancer; PI3K, phosphatidylinositol-3 kinase; PPARγ, peroxisome-proliferatoractivated receptor-γ; PR, progesterone receptor; PSA, prostate-specific antigen; PTEN, phosphatase and tensin homolog; Py, N-methylpyrrole; RNAP2, RNA polymerase II; SAR, structure-activity relationship; SPOP, speckle-type POZ protein; STAT, signal transducer and activator of transcription; TAD, transactivation domain; TMPRSS, transmembrane protease serine 2. vivo data found for each compound and the apparent limitations and/or potential for further development of these agents as PCa therapies. K E Y W O R D S androgen receptor, androgen receptor degradation, androgen receptor signaling axis, androgen receptor DNA-binding domain, androgen receptor transactivation domain, castration-resistant prostate cancer, prostate cancer 1 | INTRODUCTION 1.1 | Physiologic role and regulation of the androgen receptor The androgen receptor (AR) is a ligand-activated DNA-binding transcription factor of 110 kDa molecular weight, which facilitates the expression of androgen-dependent gene products (Figure 1). 1,2 As a member of the steroid and nuclear hormone receptor (NHR) super family, it shares many structural and functional features with other receptors such as the glucocorticoid receptor (GR), estrogen receptor (ER), mineralocorticoid receptor, progesterone receptor (PR), and the vitamin D receptor. 3,4 The nuclear steroid receptors consist of three principal domains: (1) the carboxy-terminal ligandbinding domain (...

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Tissue control of androgen action: The ups and downs of androgen receptor expression

Cited by 40 publications

References 109 publications

Importance of the Androgen Receptor Signaling in Gene Transactivation and Transrepression for Pubertal Maturation of the Testis

Importance of the Androgen Receptor Signaling in Gene Transactivation and Transrepression for Pubertal Maturation of the Testis

Polyamine pathway is associated with muscle anabolic effects by androgen receptor ligand

Molecules targeting the androgen receptor (AR) signaling axis beyond the AR‐Ligand binding domain

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