Disease- and treatment-associated acquired glucocorticoid resistance

Abstract

The development of resistance to glucocorticoids (GCs) in therapeutic regimens poses a major threat. Generally, GC resistance is congenital or acquired over time as a result of disease progression, prolonged GC treatment or, in some cases, both. Essentially, disruptions in the function and/or pool of the glucocorticoid receptor α (GRα) underlie this resistance. Many studies have detailed how alterations in GRα function lead to diminished GC sensitivity; however, the current review highlights the wealth of data concerning reductions in the GRα pool, mediated by disease-associated and treatment-associated effects, which contribute to a significant decrease in GC sensitivity. Additionally, the current understanding of the molecular mechanisms involved in driving reductions in the GRα pool is discussed. After highlighting the importance of maintaining the level of the GRα pool to combat GC resistance, we present current strategies and argue that future strategies to prevent GC resistance should involve biased ligands with a predisposition for reduced GR dimerization, a strategy originally proposed as the SEMOGRAM-SEDIGRAM concept to reduce the side-effect profile of GCs.

Keywords: GRα downregulation; acquired resistance; biased ligands; glucocorticoid receptor; glucocorticoid resistance.

Figure 1

Regulation of the GRα protein pool described by a simple ‘push’ vs ‘pull’ mechanism.

Figure 2

Post-translational modification sites of human GRα with focus on phosphorylation, ubiquitination and sumoylation. The human GRα protein consists of 777 amino acids and undergoes PTMS at numerous sites. Moreover, many of these PTM sites are contained within the N-terminal domain (NTD) (amino acids 1 to 421) of the receptor, with two present in close proximity to the DNA-binding domain (DBD) (amino acids 421 to 486). Specifically, phosphorylation (P) occurs at serine (e.g. S211, S226 and S404) residues, whilst ubiquitination (U) and sumoylation (S) occurs at lysine residues (i.e. K419 and K277, K293 and K703, respectively). Unlike the others, the K703 sumoylation site occurs within the ligand-binding domain (LBD) of the receptor (amino acids 526 to 777). Moreover, PTMs at these sites are known to modulate GRα function (white) or protein expression (red) and in some cases affect both receptor function and protein expression (pink).

Figure 3

The ubiquitination of a substrate requires multiple rounds of a multi-step enzymatic process before being targeted to the proteasome. 1. Ubiquitin (U) is activated by an activating enzyme (E1) in an energy (ATP)-dependent manner. 2. The activated U molecule is then transferred to E2, a conjugating enzyme. 3. E3 binds the substrate and the E2 and the transfer of the activated U molecule from E2 to the substrate occurs. 4. This is repeated, until a poly-ubiquitinated chain is formed and the ubiquitinated substrate is then actively (i.e. ATP-dependent) delivered to the proteasome. 5. The catalytically active proteasome recognizes and degrades the substrate to produce inactive protein fragments.

Figure 4

A ‘continuum of GC resistance’. As GRα dimerization increases, so increased ligand-induced receptor turnover of the GRα pool, both at the mRNA and protein level, occurs. These significant reductions in receptor turnover, in many cases, drive the development of an acquired resistance to treatment and so the ability of a patient to respond to treatment diminishes.