Constitutive activation of phosphatidyl-inositide 3 kinase contributes to the survival of Hodgkin's lymphoma cells through a mechanism involving Akt kinase and mTOR

Dutton, Amanda; Reynolds, Gary; Dawson, Christopher W.; Young, Lawrence S.; Murray, Paul G.

doi:10.1002/path.1725

Cited by 162 publications

(132 citation statements)

References 39 publications

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“…This antiproliferative activity is due to deregulation of several survival proteins, including Akt and ERK (19,39,40). 17-AAG rapidly and completely depleted Akt from the HD-LM2 and L-428 cell lines, which was recently reported to promote Hodgkin's lymphoma cell survival (39,40). The ability of 17-AAG to dephosphorylate ERK is likely to be induced by upstream inhibition of HSP90-client proteins, such as mitogen-activated protein kinase/ERK kinase and raf (41 -43).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Heat Shock Protein 90 Function by 17-Allylamino-17-Demethoxy-Geldanamycin in Hodgkin's Lymphoma Cells Down-Regulates Akt Kinase, Dephosphorylates Extracellular Signal–Regulated Kinase, and Induces Cell Cycle Arrest and Cell Death

Georgakis¹,

Yang²,

Rassidakis

et al. 2006

Clinical Cancer Research

114

100

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Purpose: Heat shock protein 90 (HSP90) is a chaperone for several client proteins involved in transcriptional regulation, signal transduction, and cell cycle control. HSP90 is abundantly expressed by a variety of tumor types and has been recently targeted for cancer therapy. The objective of this study was to determine the role of HSP90 in promoting growth and survival of Hodgkin's lymphoma and to determine the molecular consequences of inhibiting HSP90 function by the small-molecule 17-allylamino-17-demethoxy-geldanamycin (17-AAG) in Hodgkin's lymphoma. Experimental Design: HSP90 expression in Hodgkin's lymphoma cell lines was determined by Western blot and in primary lymph node sections from patients with Hodgkin's lymphoma by immunohistochemistry. Cell viability was determined by the 3-(4,5-dimethyl-thiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Apoptosis and cell cycle fractions were determined by flow cytometry. Expression of intracellular proteins was determined by Western blot. Results: HSP90 is overexpressed in primary and cultured Hodgkin's lymphoma cells. Inhibition of HSP90 function by 17-AAG showed a time-and dose-dependent growth inhibition of Hodgkin's lymphoma cell lines.17-AAG induced cell cycle arrest and apoptosis, which were associated with a decrease in cyclin-dependent kinase (CDK) 4, CDK 6, and polo-like kinase1 (PLK1), and induced apoptosis by caspase-dependent and caspase-independent mechanisms. Furthermore, 17-AAG depleted cellular contents of Akt, decreased extracellular signal^regulated kinase (ERK) phosphorylation, and reduced cellular FLICE-like inhibitory protein levels (FLIP), and thus enhanced the cytotoxic effect of doxorubicin and agonistic anti^tumor necrosis factor^related apoptosisinducing ligand (TRAIL) death receptor antibodies. Conclusion: Inhibition of HSP90 function induces cell death and enhances the activity of chemotherapy and anti^tumor necrosis factor^related apoptosis-inducing ligand death receptor antibodies, suggesting that targeting HSP90 function might be of therapeutic value in Hodgkin's lymphoma.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Heat Shock Protein 90 Function by 17-Allylamino-17-Demethoxy-Geldanamycin in Hodgkin's Lymphoma Cells Down-Regulates Akt Kinase, Dephosphorylates Extracellular Signal–Regulated Kinase, and Induces Cell Cycle Arrest and Cell Death

Georgakis¹,

Yang²,

Rassidakis

et al. 2006

Clinical Cancer Research

114

100

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“…51,52 Activated p70S6K was detected primarily in the nucleus, and such localization has been reported in a subset of Hodgkin's lymphomas. 53 Interestingly, activated p70S6K expression was widely expressed in MCL. This is not unexpected, because p70S6K can be activated independently of mTOR by other pathways, such as the mitogen-activated protein kinase pathway.…”

Section: Discussionmentioning

confidence: 99%

Activation of Mammalian Target of Rapamycin Signaling Promotes Cell Cycle Progression and Protects Cells from Apoptosis in Mantle Cell Lymphoma

Peponi

Δράκος

Reyes

et al. 2006

The American Journal of Pathology

111

108

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Mantle cell lymphoma (MCL) is characterized by the t(11;14) and cyclin D1 overexpression. However, additional molecular events are most likely required for oncogenesis, possibly through cell cycle and apoptosis deregulation. We hypothesized that mammalian target of rapamycin (mTOR) is activated in MCL and contributes to tumor proliferation and survival. In MCL cell lines, pharmacological inhibition of the phosphoinositide 3-kinase/AKT pathway was associated with decreased phosphorylation (activation) of mTOR and its downstream targets phosphorylated (p)-4E-BP1, p-p70S6 kinase, and p-ribosomal protein S6, resulting in apoptosis and cell cycle arrest. These changes were associated with down-regulation of cyclin D1 and the anti-apoptotic proteins cFLIP, BCL-XL, and MCL-1. Furthermore, silencing of mTOR expression using mTOR-specific short interfering RNA decreased phosphorylation of mTOR signaling proteins and induced cell cycle arrest and apoptosis. Silencing of eukaryotic initiation factor (eIF4E), a downstream effector of mTOR, recapitulated these results. We also assessed mTOR signaling in MCL tumors using immunohistochemical methods and a tissue microarray: 10 of 30 (33%) expressed Ser473 p-AKT, 13 of 21 (62%) Ser2448 p-mTOR, 22 of 22 (100%) p-p70S6K, and 5 of 20 (25%) p-ribosomal protein S6. Total eIF4E binding protein 1 and eukaryotic initiation factor 4E were expressed in 13 of 14 (93%) and 16 of 29 (55%) MCL tumors, respectively. These findings suggest that the mTOR signaling pathway is activated and may contribute to cell cycle progression and tumor cell survival in MCL.

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“…26 Two important signalling pathways, the PI3K/AKT and the MEK1/2/ERK1/2 pathways, which are activated by several different types of receptors, among them RTKs, integrins, cytokine and G-protein-coupled receptors, are constitutively activated in HRS cell lines and also in the majority of primary cases. 28,29 Although the PI3K/AKT pathway usually inhibits apoptosis and promotes cell cycle progression and proliferation, the consequences of the activation in HRS cells are currently unclear. 28 Activation of the MEK/ERK pathway leads to the phosphorylation and activation of several transcription factors, and experiments with a MEK inhibitor in HRS cell lines point to an important role in the regulation of HRS-cell survival and proliferation.…”

Section: Aberrant Activation Of Multiple Signalling Pathways In Hrs Cmentioning

confidence: 99%

Molecular biology of Hodgkin's and Reed/Sternberg cells in Hodgkin's lymphoma

Bräuninger

Schmitz

Bechtel

et al. 2005

Intl Journal of Cancer

169

116

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Hodgkin's and Reed/Sternberg (HRS) cells, the tumour cells in classical Hodgkin's lymphoma (HL), represent transformed B cells in nearly all cases. The detection of destructive somatic mutations in the rearranged immunoglobulin (Ig) genes of HRS cells in classical HL indicated that they originate from preapoptotic germinal centre (GC) B cells that lost the capacity to express a highaffinity B-cell receptor (BCR). Several aberrantly activated signalling pathways and transcription factors have been identified that contribute to the rescue of HRS cells from apoptosis. Among the deregulated signalling pathways, activation of multiple receptor tyrosine kinases in HRS cells appears to be a specific feature of HL. In about 40% of cases of classical HL the HRS cells are infected by Epstein-Barr virus (EBV), indicating an important role of EBV in HL pathogenesis. Interestingly, nearly all cases of HL with destructive Ig gene mutations eliminating BCR expression (e.g. nonsense mutations) are EBV-positive, suggesting that EBV-encoded genes have a particular function to prevent apoptosis of HRS-cell precursors that acquired such crippling mutations. This idea is further supported by the recent demonstration that isolated human GC B cells harbouring crippled Ig genes can be rescued by EBV from cell death, giving rise to lymphoblastoid cell lines. The molecular analysis of composite Hodgkin's and nonHodgkin's lymphomas indicated that many cases develop from a common GC B-cell precursor in a multistep transformation process with both shared and distinct oncogenic events. 2-6 Nearly all cases of classical and lymphocyte-predominance HL carry somatically mutated V genes, suggesting an origin from (post) germinal centre (GC) B cells, as somatic hypermutation of Ig V genes specifically takes place in GC B cells.7 In lymphocyte-predominance HL, the detection of intraclonal V gene diversity and several phenotypic features suggest an origin of the L&H cells from mutating and selected GC B cells. 2,4,5 In classical HL, crippling mutations that destroyed the coding capacity of originally functional rearrangements were detected in about a quarter of cases.3,8 Such obviously crippling mutations happen in mutating GC B cells, but represent only a small fraction of all disadvantagous mutations that normally result in apoptosis of the respective GC B cells. In the GC, there is a stringent selection for B cells acquiring affinity-increasing mutations, so also many GC B cells that still express a B-cell receptor (BCR) but which fails to bind to the cognate antigen with improved affinity will undergo apoptosis.9,10 Thus, we speculated that the vast majority of HRS cells in classical HL are derived from preapoptotic GC B cells. 3 In rare cases (about 2%) HRS cells originate from T cells. 11,12 Although HRS cells are usually transformed B cells, global gene expression analysis of HRS cell lines using microarrays revealed that the HRS cells have lost the expression of most B-cell markers to an extent that is unique among B-cell lymphomas. 13 As t...

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Constitutive activation of phosphatidyl-inositide 3 kinase contributes to the survival of Hodgkin's lymphoma cells through a mechanism involving Akt kinase and mTOR

Cited by 162 publications

References 39 publications

Inhibition of Heat Shock Protein 90 Function by 17-Allylamino-17-Demethoxy-Geldanamycin in Hodgkin's Lymphoma Cells Down-Regulates Akt Kinase, Dephosphorylates Extracellular Signal–Regulated Kinase, and Induces Cell Cycle Arrest and Cell Death

Inhibition of Heat Shock Protein 90 Function by 17-Allylamino-17-Demethoxy-Geldanamycin in Hodgkin's Lymphoma Cells Down-Regulates Akt Kinase, Dephosphorylates Extracellular Signal–Regulated Kinase, and Induces Cell Cycle Arrest and Cell Death

Activation of Mammalian Target of Rapamycin Signaling Promotes Cell Cycle Progression and Protects Cells from Apoptosis in Mantle Cell Lymphoma

Molecular biology of Hodgkin's and Reed/Sternberg cells in Hodgkin's lymphoma

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