Molecular Mechanisms Conferring Resistance/Sensitivity to Glucocorticoid-Induced Apoptosis

Berrou, Ilhem; Krstic‐Demonacos, Marija; Demonacos, Constantinos

doi:10.5772/51467

Cited by 2 publications

(2 citation statements)

References 148 publications

(176 reference statements)

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“…Necrosome formation via stimulation of TRAIL/TNF activates RIPK3 which interacts with enzymes regulating glycolytic flux and glutaminolysis [ 68 ]. Reactive oxygen species ultimately form, whilst redox status is important in determining sensitivity to microenvironment and chemotherapy [ 35 , 67 – 69 ]. RIPK1 substrates are yet to be identified as are factors necessary for cell death induction through necroptosis or apoptosis [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

Differential regulation of cell death pathways by the microenvironment correlates with chemoresistance and survival in leukaemia

et al. 2017

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Glucocorticoids (GCs) and topoisomerase II inhibitors are used to treat acute lymphoblastic leukaemia (ALL) as they induce death in lymphoid cells through the glucocorticoid receptor (GR) and p53 respectively. Mechanisms underlying ALL cell death and the contribution of the bone marrow microenvironment to drug response/resistance remain unclear. The role of the microenvironment and the identification of chemoresistance determinants were studied by transcriptomic analysis in ALL cells treated with Dexamethasone (Dex), and Etoposide (Etop) grown in the presence or absence of bone marrow conditioned media (CM). The necroptotic (RIPK1) and the apoptotic (caspase-8/3) markers were downregulated by CM, whereas the inhibitory effects of chemotherapy on the autophagy marker Beclin-1 (BECN1) were reduced suggesting CM exerts cytoprotective effects. GCs upregulated the RIPK1 ubiquitinating factor BIRC3 (cIAP2), in GC-sensitive (CEM-C7-14) but not in resistant (CEM-C1-15) cells. In addition, CM selectively affected GR phosphorylation in a site and cell-specific manner. GR is recruited to RIPK1, BECN1 and BIRC3 promoters in the sensitive but not in the resistant cells with phosphorylated GR forms being generally less recruited in the presence of hormone. FACS analysis and caspase-8 assays demonstrated that CM promoted a pro-survival trend. High molecular weight proteins reacting with the RIPK1 antibody were modified upon incubation with the BIRC3 inhibitor AT406 in CEM-C7-14 cells suggesting that they represent ubiquitinated forms of RIPK1. Our data suggest that there is a correlation between microenvironment-induced ALL proliferation and altered response to chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Differential regulation of cell death pathways by the microenvironment correlates with chemoresistance and survival in leukaemia

et al. 2017

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“…Several gene mutations and hazardous environmental factors (including radiation and toxic chemical exposure) are associated with ALL in children (4,5). Factors affecting the Endoplasmic reticulum stress, unfolded protein response and autophagy contribute to resistance to glucocorticoid treatment in human acute lymphoblastic leukaemia cells development of resistance to ALL treatment include genetic variability in xenobiotic metabolism (6), prevalence of a GC receptor (GR)β splicing variant (7), upregulation of the antiapoptotic Bcl-2 family proteins (8), differential phosphorylation of GR in dex-induced apoptosis-resistant vs. sensitive ALL cells (9), alterations in dNA repair pathways (10) and cell cycle checkpoint defects (11).…”

Section: Introductionmentioning

confidence: 99%

Endoplasmic reticulum stress, unfolded protein response and autophagy contribute to resistance to glucocorticoid treatment in human acute lymphoblastic leukaemia cells

et al. 2020

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Acute lymphoblastic leukaemia (ALL) is the most frequent childhood cancer and, although it is highly treatable, resistance to therapy, toxicity and side effects remain challenging. The synthetic glucocorticoid (GC) dexamethasone (dex) is commonly used to treat ALL, the main drawback of which is the development of resistance to this treatment. The aim of the present study was to investigate potential molecular circuits mediating resistance and sensitivity to GC-induced apoptosis in ALL. The leukaemia cell lines CEM-C7-14, CEM-C1-15 and MOLT4 treated with chloroquine (CLQ), thapsigargin (TG) and rotenone (ROT) were used to explore the roles of autophagy, endoplasmic reticulum (ER) stress/unfolded protein response (UPR) and reactive oxygen species (ROS) generation in the response to GC treatment. ROS levels were associated with increased cell death and mitochondrial membrane potential in rotenone-treated CEM cells. Autophagy inhibition by CLQ exhibited the strongest cytotoxic effect in GC-resistant leukaemia. Autophagy may act as a pro-survival mechanism in GC-resistant leukaemia since increasing trends in beclin-1 and microtubule-associated protein 1 light chain 3α levels were detected in CEM-C1-15 and MOLT4 cells treated with dex, whereas decreasing trends in these autophagy markers were observed in CEM-C7-14 cells. The intracellular protein levels of the ER stress markers glucose-regulated protein (GRP)78 and GRP94 were stimulated by dex only in the GC-sensitive cells, suggesting a role of these chaperones in the GC-mediated ALL cell death. Increased cell surface levels of GRP94 were recorded in CEM-C7-14 cells treated with combination of dex with TG compared with those in cells treated with TG alone, whereas decreasing trends were observed in CEM-C1-15 cells under these conditions. Taken together, the results of the present study demonstrated that autophagy may be a pro-survival mechanism in GC-resistant leukaemia, and by modulating intracellular and surface GRP94 protein levels, dex is involved in the regulation of ER stress/UPR-dependent cell death and immune surveillance. These observations may be of clinical importance if confirmed in patients.

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Molecular Mechanisms Conferring Resistance/Sensitivity to Glucocorticoid-Induced Apoptosis

Cited by 2 publications

References 148 publications

Differential regulation of cell death pathways by the microenvironment correlates with chemoresistance and survival in leukaemia

Differential regulation of cell death pathways by the microenvironment correlates with chemoresistance and survival in leukaemia

Endoplasmic reticulum stress, unfolded protein response and autophagy contribute to resistance to glucocorticoid treatment in human acute lymphoblastic leukaemia cells

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