Disease- and treatment-associated acquired glucocorticoid resistance

Wilkinson, Legh; Verhoog, Nicolette; Louw, Ann

doi:10.1530/ec-18-0421

Cited by 41 publications

(45 citation statements)

References 193 publications

(405 reference statements)

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“…Second, some patients are refractory to the therapy and are GC resistant (GCR). GCR can either be inherited, mostly via mutations in the NR3C1 gene (52, 164), or acquired (165). The latter can be caused by ligand induced homologous downregulation of the GR, caused chronical GC treatment (166, 167), or by pathophysiological processes accompanying the inflammatory disease states [e.g., chronic obstructive pulmonary disease (COPD) (168), SLE (169)].…”

Section: Gc Therapy: Drawbacks and Optimizationmentioning

confidence: 99%

A General Introduction to Glucocorticoid Biology

2019

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Glucocorticoids (GCs) are steroid hormones widely used for the treatment of inflammation, autoimmune diseases, and cancer. To exert their broad physiological and therapeutic effects, GCs bind to the GC receptor (GR) which belongs to the nuclear receptor superfamily of transcription factors. Despite their success, GCs are hindered by the occurrence of side effects and glucocorticoid resistance (GCR). Increased knowledge on GC and GR biology together with a better understanding of the molecular mechanisms underlying the GC side effects and GCR are necessary for improved GC therapy development. We here provide a general overview on the current insights in GC biology with a focus on GC synthesis, regulation and physiology, role in inflammation inhibition, and on GR function and plasticity. Furthermore, novel and selective therapeutic strategies are proposed based on recently recognized distinct molecular mechanisms of the GR. We will explain the SEDIGRAM concept, which was launched based on our research results.

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Section: Gc Therapy: Drawbacks and Optimizationmentioning

confidence: 99%

A General Introduction to Glucocorticoid Biology

2019

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“…Clearly, further experimental work is needed to fully clarify the physiologically relevant conformation(s) of the GR and other members of the oxosteroid subfamily to integrate structural, biochemical and cellular studies ( Fig. 3) (Bledsoe et al 2002, Kauppi et al 2003, Robertson et al 2013a,b, Presman et al 2016, 2017, Paakinaho et al 2017, Weikum et al 2017, Wilkinson et al 2018.…”

Section: Quaternary Structure Of the Ar-lbd: Functional Implicationsmentioning

confidence: 99%

“…In turn, HPA overactivation leads to hypersecretion of ACTH and cortisol (highly variable, ranging from severe symptoms to subclinical hypercortisolism) and may result in increased production of other adrenal steroids such as androgens and mineralocorticoids. Patients affected by this syndrome are thus commonly diagnosed by clinical signs of mineralocorticoid and/or androgen excess (hypertension due to hyperaldosteronism and/or hyperandrogenic signs), rather than those associated with GC deficiency (Kino & Chrousos 2001, Kino et al 2002, Nicolaides et al 2010, 2015a,b, Charmandari et al 2013, Nicolaides & Charmandari 2015, Wilkinson et al 2018.…”

Section: Nr3c1/gr Mutations Linked To Either Glucocorticoid Resistancmentioning

confidence: 99%

Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease

Jiménez-Panizo

Pérez

Rojas

et al. 2019

Endocrine-Related Cancer

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Nuclear receptors are transcription factors that play critical roles in development, homeostasis and metabolism in all multicellular organisms. An important family of nuclear receptors comprises those members that respond to steroid hormones, and which is subdivided in turn into estrogen receptor (ER) isoforms α and β (NR3A1 and A2, respectively), and a second subfamily of so-called oxosteroid receptors. The latter includes the androgen receptor (AR/NR3C4), the glucocorticoid receptor (GR/NR3C1), the mineralocorticoid receptor (MR/NR3C2) and the progesterone receptor (PR/NR3C3). Here we review recent advances in our understanding of the structure-and-function relationship of steroid nuclear receptors and discuss their implications for the etiology of human diseases. We focus in particular on the role played by AR dysregulation in both prostate cancer (PCa) and androgen insensitivity syndromes (AIS), but also discuss conditions linked to mutations of the GR gene as well as those in a non-steroidal receptor, the thyroid hormone receptor (TR). Finally, we explore how these recent results might be exploited for the development of novel and selective therapeutic strategies.

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“…Pharmacologically, glucocorticoids are a cost-effective effective therapy for inflammatory and autoimmune diseases and are widely prescribed (1–3). Despite the effectiveness of glucocorticoids in treating inflammation chronic use causes side-effects (4) and acquired glucocorticoid resistance (5, 6). The design of drugs with fewer side-effects and less potential for the development of resistance is therefore considered crucial for improved therapy (7).…”

Section: Introductionmentioning

confidence: 99%

GR Dimerization and the Impact of GR Dimerization on GR Protein Stability and Half-Life

Louw

2019

Front. Immunol.

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Pharmacologically, glucocorticoids, which mediate their effects via the glucocorticoid receptor (GR), are a most effective therapy for inflammatory diseases despite the fact that chronic use causes side-effects and acquired GC resistance. The design of drugs with fewer side-effects and less potential for the development of resistance is therefore considered crucial for improved therapy. Dimerization of the GR is an integral step in glucocorticoid signaling and has been identified as a possible molecular site to target for drug development of anti-inflammatory drugs with an improved therapeutic index. Most of the current understanding regarding the role of GR dimerization in GC signaling derives for dimerization deficient mutants, although the role of ligands biased toward monomerization has also been described. Even though designing for loss of dimerization has mostly been applied for reduction of side-effect profile, designing for loss of dimerization may also be a fruitful strategy for the development of GC drugs with less potential to develop GC resistance. GC-induced resistance affects up to 30% of users and is due to a reduction in the GR functional pool. Several molecular mechanisms of GC-mediated reductions in GR pool have been described, one of which is the autologous down-regulation of GR density by the ubiquitin-proteasome-system (UPS). Loss of GR dimerization prevents autologous down-regulation of the receptor through modulation of interactions with components of the UPS and post-translational modifications (PTMs), such as phosphorylation, which prime the GR for degradation. Rational design of conformationally biased ligands that select for a monomeric GR conformation, which increases GC sensitivity through improving GR protein stability and increasing half-life, may be a productive avenue to explore. However, potential drawbacks to this approach should be considered as well as the advantages and disadvantages in chronic vs. acute treatment regimes.

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Disease- and treatment-associated acquired glucocorticoid resistance

Cited by 41 publications

References 193 publications

A General Introduction to Glucocorticoid Biology

A General Introduction to Glucocorticoid Biology

Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease

GR Dimerization and the Impact of GR Dimerization on GR Protein Stability and Half-Life

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