JOP. J Pancreas (Online) 2015 Jan 31; 16(1):11-19 REVIEW ARTICLE Glucococorticoid-Induced Death of Pancreatic Beta Cells: An Organized Chaos Joselyn Rojas1,2, Mervin Chávez Castillo1, Mayela Cabrera1, Valmore Bermúdez1 1Endocrine and Metabolic Diseases Research Center, School of Medicine the University of Zulia, Maracaibo and 2Institute of Clinical Immunology, Los Andes University, Mérida - Venezuela ABSTRACT Glucocorticoids (GC) are renowned for their pleiotropic effects in all organ systems, their ubiquitous use in numerous clinical settings, and the abundant adverse effects they may exert, particularly in the endocrine-metabolic sphere. Although hyperglycemia and insulin resistance are well-defined GC-induced diabetogenic phenomena, an added component of direct injury to pancreatic β cells (PBC) may also participate in this scenario. Indeed, the apoptotic capacity of GC is widely recognized, and PBC do not escape this situation. No unified- pathway has been characterized regarding GC-induced cell death; instead, it appears to depend on the specific machinery of each cell type, determining a great heterogeneity in GC-dependent apoptotic mechanisms among different tissues. In PBC, GC can induce the expres- sion or activation of pro-apoptotic proteins (Bax, BAD, p38), repress anti-apoptotic proteins (Bcl-2), deactivate pro-survival mechanisms anti-proliferative(cAMP-PKA signaling) mechanisms and sensitize appear the to cell eventually to death overcome induced by their oxidative pro-survival stress, counterparts, fatty acids, hyperglycemia due to their synergic and cytokines. and aggregative Although action.prolif erative pathways (TGF-β, H-ras) are activated simultaneously –and an increase in PBC mass may be observed initially– pro-apoptotic and Key molecules such as p38 and the cAMP-PKA system may be promising therapeutic targets in the prevention of GC-induced cell death. INTRODUCTION Indeed, although the pro-apoptotic effects of GC have been profoundly studied in many tissues, and subsequently Glucocorticoids (GC) are steroid hormones essential to exploited in the management of GC-sensitive cancers homeostasis of multiple organ systems, with glucocorticoid receptors (GR) present in virtually all human cells [1, 2]. In such as small-cell lung carcinoma [10] osteosarcoma [11] everyday clinical settings, their pharmacologic analogues and lymphoid malignancies [12]; yet their implications are frequently used principally due to their powerful anti- in the regulation of survival of other cell types may be ubiquity of GR conveys the main and most controversial inflammatory attributes, among other effects [3]. The tisular aimsoverwhelmingly to offer an integrateddeleterious, vision especially of the inmain PBC, molecular due to catalogue of adverse consequences in various spheres their paramount role in metabolism [13]. This review [4].disadvantage Their deleterious of their use:impact A well-knownon energetic and metabolism extensive and glycemic status are particularly preoccupying, as they hypotheses and findings underlying GC-induced cell death GLUCOCORTICOID SIGNALING – PHYSIOLOGIC can not only directly induce hyperglycemia [5], but also in PBC. potentiate this process by favoring development of insulin ASPECTS genetic induction and/or repression [14], and although roleresistance of GC [6];as potentialand modulate inductors proliferation of secondary and total Diabetes mass novelMuch likenon-genomic other steroid mechanisms hormones, GChave act mainlyrecently through been of pancreatic β cells (PBC) [7]. These properties define the described [15], these have not yet been described to be related to cell survival/death. In contrast, the genomic Mellitus in certain scenarios [8]. The direct impact of GC in PBC is particularly concerning because –as with other mechanisms of GC have been extensively studied (Figure effects of GC on carbohydrate and lipid metabolism– it may 1), culminating in binding of GC-GR complexes to genomic sequences termed Glucocorticoid Response Elements, notReceived be fully reversible [9]. Accepted Key words with association of co-activator and co-repressor proteins, beta cell agenesis October with 15th, neonatal 2014 – diabetes mellitusNovember 28th, 2014 Abbreviations Apoptosis; GC Glucocorticoids Cell Death; Glucocorticoids; Pancreatic transcriptionresulting in facilitation factors through or prevention protein-protein of DNA transcription interactions, Correspondence [16, 17]. In addition, GR may sequester various UniversityPBC Pancreatic of Zulia, β cells School of Medicine, Endocrine and Metabo- lic Diseases Research Joselyn Center, Rojas includingThe properties Nuclear of GRFactor also κB determine (NFκB) [18]. cell sensitivity to GC. Maracaibo, Venezuela Phone Fax tGR are codified in a single locus (5q31.3; OMIM: 138040), E-mail +58-261-7597279 +58-261-7597279 in 9 distinct exons [18]. Alternative splicing of exon 9 yields [email protected] wo transcription isoforms, GRα and GRβ. While GRα is the JOP. Journal of the Pancreas - http://www.serena.unina.it/index.php/jop - Vol. 16 No. 1 – Jan 2015. [ISSN 1590-8577] 11 JOP. J Pancreas (Online) 2015 Jan 31; 16(1):11-19 GC CYTOSOL GC GR GC + GR GC GR GC HSP90 GR GC GR CO-ACTIVATORS CO-REPRESSORS HSP90 GR GC GR GC GLUCOCORTICOID RESPONSE ELEMENTS TRANSACTIVATIÓN TRANSREPRESSION NUCLEUS GC: Glucocorticoid; HSP90: Heat Shock Protein 90; RG: Glucocorticoid Receptor. After entering the cytosol, GC bind to GR, which is held in its inactive form by chaperone proteins, notably HSP90. Formation of the GR-GC complex prompts conformational modifications in the structure of GR, leading to separation from chaperones and dimerization with other com- plexes. GR-GC dimers can then translocate to the nucleus, bind to Glucocorticoid Response Elements, and interact with nuclear co-activator and/or co-repressor proteins. This results in tansactivation or transrepression of myriad of GC-modulated genes, variable in each cell type. Figure 1. Genomic mechanism of action of glucocorticoids. In this aspect, GC are thought to predominantly utilize the is unable to initiate transcription, despite being able to intrinsic apoptotic pathway, as they appear inoffensive key mediator in the classical model of GC signaling, GRβ to GC, which have been observed to undergo apoptosis homodimerize and bind to DNA [19]. Moreover, GRβ may to this cascade, as seen in pre-B leukemic cells exposed interfere with GRα activity through heterodimerization. resistanceThus, GRβ [20].is an On important the other hand,modulator initiation of GC of translationsensitivity, extrinsiceven after pathway treatment [24]. withMoreover, Cytokine they Responsemay in fact Modifier prevent thewith GR increased transcript expression may occur of atthis four isoform distinct linked sites to(A-D) GC apoptosisA (crmA), bya interferingcaspase-8 inhibitor,with the extrinsic a key mediator counterpart, in the as located in exon 2, yielding various translation isoforms they have been proved to inhibit expression of Fas-L in T (Figure 2). In consequence, although exon 1 remains cell hibridomas [25]. behavior of GC intracellular signaling. Finally, in regards to In contrast, the impact of GC on the intrinsic pathway is untranslated, these variations heavily influence the better understood, and relies mainly on the differential to be the most and least powerful, respectively [21]. induction of apoptosis, isoforms RGα-C and RGα-D appear DIFFERENT STROKES FOR DIFFERENT CELLS xL)induction proteins, or modifyingrepression a cellularof pro-apoptotic “rheostat” which(Bid, mayBax, Impact of Glucocorticoids on Regulation of Cell Bim, Bad, Puma, Noxa) and anti-apoptotic (Bcl-2, Bcl- Survival/Death apoptotic proteins leads to cell death primarily through favor cell survival or death [26]. Predominance of pro- Glucocorticoids play a unique role in relation to regulation mitochondrial mechanisms, especially the release of of cell survival, as they can act as both pro- and anti- apoptotic signals in different cell types. Indeed, they have cytochrome c, which activates caspase-9 and thus renders been documented as inductors of cell death in various modifying this balance are widely variable amongst cell cell death imminent [27]. However, the molecular events tissues [12], yet have also been observed to inhibit this types [12]. process in select cells, such as neutrophils [22] and Activation of GR appears to be a fundamental event for GC-induced apoptosis, as cell lineages with mutated GR instead,granulosa GC cells appear [23]. to These exploit steroids each cell’sare also autochthonous notable for lacking a distinct, universal apoptogenic mechanism; seem resistant to this fate [28]. Likewise, downregulation molecular cascades [12). of 11β-hydroxysteroid dehydrogenase –which converts machinery, originating highly cell-specific pro-apoptotic cortisol to inactive cortisone – sensitizes cells to GC- induced apoptosis [29]. Furthermore, the susceptibility to JOP. Journal of the Pancreas - http://www.serena.unina.it/index.php/jop - Vol. 16 No. 1 – Jan 2015. [ISSN 1590-8577] 12 JOP. J Pancreas (Online) 2015 Jan 31; 16(1):11-19 Translation Initiation Sites A B C D 1 2 3 4 5 6 7 8 9α 9β N-Terminal Domain DBD Ligand-Binding Domain α Transcriptional Isoforms N-Terminal Domain DBD Ligand-Binding Domain β DBD: DNA-Binding Domain. The glucocorticoid receptor gene is constituted by 9 exons, which originate 4 domains. The final domain (α or β) is determined by alternative splicing of exon 9, yielding transcriptional isoforms with contrasting properties.