Staurosporine Sensitizes T Lymphoma Cells to Glucocorticoid-Induced Apoptosis: Role of Nur77 and Bcl-2

Kfir, Shlomit; Sionov, Ronit Vogt; Zafrir, Elazar; Zilberman, Yoram; Yefenof, Eitan

doi:10.4161/cc.6.24.5023

Cited by 14 publications

(27 citation statements)

References 41 publications

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“…thymocytes, CD4 ϩ 8 ϩ PD1.6 thymic lymphoma and 2B4 T cells), which undergo extensive GC-induced apoptosis within 20 h and partially resistant cells (e.g. CD4 Ϫ 8 Ϫ S49 thymic lymphoma, CD4 Ϫ 8 Ϫ B10 thymic lymphoma, and CCRF-CEM T-ALL cells), which show partial apoptotic response after 48 -72 h exposure to the GC drug dexamethasone (Dex) (1,13,32). The use of several cell types makes it possible to distinguish the common signaling pathways from idiotypic regulatory mechanisms.…”

Section: Screening For Protein Kinases Involved In Mediating Gc-inducmentioning

confidence: 99%

“…Because Cdk2-deficient thymocytes are sensitive to Dex-induced apoptosis (42), and roscovitine at high concentrations is still able to abrogate Dex-mediated cell death in these cells . Apoptosis was measured by the PI-exclusion assay, which is the most adequate assay for assessing cell death in lymphoma and leukemia cells (32). The results of the PI-exclusion assay correlate with the caspase-3 activation assay.…”

Section: Screening For Protein Kinases Involved In Mediating Gc-inducmentioning

confidence: 99%

“…Inhibition of one or more of these protein kinases may sensitize the cells to GC-induced apoptosis, suggesting that the apoptotic process is mediated by kinase-regulated signal transduction pathways. Also, the broad-acting protein kinase inhibitors staurosporine (32) and CHIR-258 (33) can sensitize GC-resistant lymphoma and multiple myeloma cells to GC-induced apoptosis, indicating that it is possible to overcome GC resistance by altering the cell's kinome.…”

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confidence: 98%

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Glycogen Synthase Kinase-3 Plays a Central Role in Mediating Glucocorticoid-Induced Apoptosis

Spokoini

Kfir‐Erenfeld

Yefenof

et al. 2010

Molecular Endocrinology

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It is still unclear how glucocorticoids (GCs) induce apoptosis of thymocytes and T lymphoma cells. Emergence of GC-resistant lymphoma cells is a major obstacle in GC therapy, emphasizing the need for novel strategies that maintain the sensitivity of lymphoma cells to the proapoptotic effects of GC. We have undertaken a kinome study to elucidate the signal transduction pathways involved in mediating GC-induced apoptosis. Our study shows that glycogen synthase kinase (GSK3) plays a central role in promoting GC-induced apoptosis. In the absence of a ligand, GSK3alpha, but not GSK3beta, is sequestered to the glucocorticoid receptor (GR). Exposure to GCs leads to dissociation of GSK3alpha from GR and subsequent interaction of GSK3alpha and GSK3beta with the proapoptotic Bim protein, an essential mediator of GC-induced apoptosis. Chemical inhibition of GSK3 by SB216763, BIO-Acetoxime, or LiCl and GSK3 inhibition using a dominant-negative mutant of GSK3 impede this cell death process, indicating that GSK3 is involved in transmitting the apoptotic signal. GC resistance in lymphoma cells can be relieved by inhibiting the phosphatidylinositol-3 kinase-Akt survival pathway, which inactivates GSK3. Notch1, a transcription factor frequently activated in T acute lymphoblastic leukemia cells, confers GC resistance through activation of Akt. Altogether, this study illuminates the link connecting upstream GR signals to the downstream mediators of GC-induced apoptosis. Our data suggest that targeting protein kinases involved in GSK3 inactivation should improve the outcome of GC therapy.

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Section: Screening For Protein Kinases Involved In Mediating Gc-inducmentioning

confidence: 99%

Section: Screening For Protein Kinases Involved In Mediating Gc-inducmentioning

confidence: 99%

mentioning

confidence: 98%

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Glycogen Synthase Kinase-3 Plays a Central Role in Mediating Glucocorticoid-Induced Apoptosis

Spokoini

Kfir‐Erenfeld

Yefenof

et al. 2010

Molecular Endocrinology

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“…For example, in leukemias of myelogenous origin, GR is down-regulated by glucocorticoids, perhaps accounting for their inherent resistance to glucocorticoid therapy (Kfir et al, 2007). Furthermore, homologous GR down-regulation is an indicator of poor prognosis in ALL (Bloomfield et al, 1981; Pui and Costlow, 1986).…”

Section: Mechanisms Of Glucocorticoid Resistance In Haematomalignanciesmentioning

confidence: 99%

Glucocorticoid-Induced Apoptosis of Healthy and Malignant Lymphocytes

Smith

Cidlowski

2010

Progress in Brain Research

124

104

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Glucocorticoids exert a wide range of physiological effects, including the induction of apoptosis in lymphocytes. The progression of glucocorticoid-induced apoptosis is a multi-component process requiring contributions from both genomic and cytoplasmic signaling events. There is significant evidence indicating that the transactivation activity of the glucocorticoid receptor is required for the initiation of glucocorticoid-induced apoptosis. However, the rapid cytoplasmic effects of glucocorticoids may also contribute to the glucocorticoid-induced apoptosis-signaling pathway. Endogenous glucocorticoids shape the T-cell repertoire through both the induction of apoptosis by neglect during thymocyte maturation and the antagonism of T-cell receptor (TCR)-induced apoptosis during positive selection. Owing to their ability to induce apoptosis in lymphocytes, synthetic glucocorticoids are widely used in the treatment of haematological malignancies. Glucocorticoid chemotherapy is limited, however, by the emergence of glucocorticoid resistance. The development of novel therapies designed to overcome glucocorticoid resistance will dramatically improve the efficacy of glucocorticoid therapy in the treatment of haematological malignancies.

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“…Resistance to Gcs can occur by downregulation of the GR following Gc treatment (Kfir et al 2007). Decreased expression of the GR may occur through decreased activity of the GR promoter, decreased mRNA stability (Schaaf & Cidlowski 2002), or decreased protein stability (Wallace & Cidlowski 2001).…”

Section: Mechanisms Of Gc Resistance In Lymphoid Malignanciesmentioning

confidence: 99%

Glucocorticoid receptor-mediated apoptosis: mechanisms of resistance in cancer cells

Schlossmacher

Stevens²,

White

2011

Journal of Endocrinology

136

110

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Glucocorticoids (Gcs) are commonly used to treat patients suffering from a wide range of cancers. Their main therapeutic role is based on Gc receptor (GR)-mediated mechanisms that trigger cell death but this varies depending on the cancer type. This review aims to provide an overview of the mechanisms of Gc-induced cell death and more importantly the changes in GR that lead to resistance to Gc treatment in cancer. The three main cancer types, which are susceptible to Gc resistance and therefore loss of Gc-induced apoptotic effects, are acute lymphoblastic leukaemia, osteosarcoma and small-cell lung carcinoma. A common theme is the loss of GR function and/or a downregulation of GR expression which leads to failure of the cell death-inducing effects of Gcs. Loss of GR function is attributed to mutations in the GR gene, and in some cases a dominant-negative effect on any functional GR still present. The downregulation of GR expression can be due to decreased GR promoter activation, increased GR promoter methylation or increased expression of alternative splice isoforms of GR that have decreased transcriptional activity. Understanding the mechanisms behind Gc-triggered apoptosis and the resistance to it in these cancer types will help in further refining treatment regimens for patients and will decrease the chance of relapse caused by Gc-resistant cancer phenotypes.

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Staurosporine Sensitizes T Lymphoma Cells to Glucocorticoid-Induced Apoptosis: Role of Nur77 and Bcl-2

Cited by 14 publications

References 41 publications

Glycogen Synthase Kinase-3 Plays a Central Role in Mediating Glucocorticoid-Induced Apoptosis

Glycogen Synthase Kinase-3 Plays a Central Role in Mediating Glucocorticoid-Induced Apoptosis

Glucocorticoid-Induced Apoptosis of Healthy and Malignant Lymphocytes

Glucocorticoid receptor-mediated apoptosis: mechanisms of resistance in cancer cells

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