Rapamycin reverses NPM-ALK-induced glucocorticoid resistance in lymphoid tumor cells by inhibiting mTOR signaling pathway, enhancing G1 cell cycle arrest and apoptosis

Gu, Ling; Gao, Ju; Li, Q; Zhu, Yi Ping; Jia, Cang-song; Fu, Ruihuan; Chen, Y; Liao, Qing-kui; Ma, Zhigui

doi:10.1038/leu.2008.204

Cited by 39 publications

(37 citation statements)

References 29 publications

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“…11 Recently, aberrations in the activation of the mTOR-signaling pathway have come to light in NHL. 12,13 An in vivo model using the mTOR inhibitor CCI-779 demonstrated apoptosis and growth suppression of primary acute lymphocytic lymphoma cells engrafted in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice, 14 providing a strong rationale for the development of mTOR-targeted therapy in lymphoid malignancies. Therefore, improved understanding of the underlying molecular mechanism(s) associated with the ability of ethanol to suppress mTOR activity may form the basis for the development of innovative approaches to prevent lymphoma growth.…”

Section: Introductionmentioning

confidence: 99%

Alcohol consumption and decreased risk of non-Hodgkin lymphoma: role of mTOR dysfunction

Hagner

Mazan-Mamczarz

Dai

et al. 2009

Blood

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Several epidemiologic studies support the emerging paradigm that current alcohol consumers have decreased risk of most types of non-Hodgkin lymphoma. The observed lower risk among people who drank alcohol does not seem to vary with beverage type. The mechanisms accounting for alcohol-induced decrease in the incidence of lymphomas remain largely unknown. We demonstrate that low-dose chronic exposure to ethanol inhibits mammalian target of rapamycin (mTOR) C1 complex formation, resulting in decreased phosphorylation events involved in mTOR pathway signaling in a lymphoid-tissue specific manner. These changes in mTOR signaling lead to a decrease in eIF4E associated with the translation initiation complex and a repression of global capdependent synthesis in both lymphoma cell lines and normal donor lymphocytes. We show that chronic exposure of ethanol at physiologically relevant concentrations in a xenograft model results in a striking inhibition of lymphoma growth. IntroductionAlcohol abuse is associated with diseases of the liver, pancreas, and breast, and many other malignant disorders. 1,2 Interestingly, in contrast to solid tumors, several epidemiologic studies, including a large pooled analysis of case-control studies 3 and a recent cohort study, 4 indicate that persons who frequently consume small amounts of alcohol (1 or 2 drinks per day) have decreased risk of most types of non-Hodgkin lymphoma (NHL). The underlying biologic mechanism(s) for this negative association is (are) unknown at present.Ethanol decreases protein synthesis, and this effect is associated with changes in the phosphorylation status of several key components of the translational machinery. 5,6 Chronic alcohol intake is associated with disruption of the mammalian target of rapamycin (mTOR) signaling pathway; however, few mechanistic details are known about how ethanol interrupts this critical signaling pathway involved in translation. 7 mTOR forms 2 functionally distinct multiprotein serine/threonine kinase complexes, mTORC1 and mTORC2. The mTORC1 complex controls protein synthesis by phosphorylating key downstream effector molecules, the translational inhibitor protein 4E-BP1 and, p70 S6 kinase in response to sensory inputs, such as nutritional, growth factor, and cellular energy status. Activation of the p70 S6 kinase results in phosphorylation of the ribosomal protein S6 (RPS6) and allows its interaction with other ribosomal subunits and ribosomal biogenesis. 8 Phosphorylation of ribosomal protein S6 by p70 S6 kinase stimulates the translation of mRNAs with a 5Ј oligopyrimidine tract, which typically encode components of the protein synthesis machinery. 8 The signaling pathways that converge on mTOR are commonly activated in multiple human malignancies. The dysregulation of mTOR signaling leads to a selective increase in translation of messages that encode antiapoptotic proteins, activators of cell cycle progression, and growth factors, such as cyclin D1 and c-myc. 9,10 This underscores the importance of targeted inhibition of mTOR as...

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Section: Introductionmentioning

confidence: 99%

Alcohol consumption and decreased risk of non-Hodgkin lymphoma: role of mTOR dysfunction

Hagner

Mazan-Mamczarz

Dai

et al. 2009

Blood

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“…mTOR can participate in the regulation of neuronal death. mTOR inhibition by rapamycin can suppress the activation of cyclin-dependent kinases and then inhibits the cell cycle progress, suppresses cell proliferation, and fi nally results in cell apoptosis (Gu et al 2008 ).…”

Section: Hypoxic-ischemic Brain Damage and Tryptophanmentioning

confidence: 99%

Tryptophan and Cell Death

Engin¹

2015

Tryptophan Metabolism: Implications for Biological Processes, Health and Disease

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Cell death attributed to the tryptophan (Trp) metabolites is dependent on the exposure time and intracellular concentrations of cytotoxic Trp derivatives such as 3-hydroxykynurenine (3HK), 3-hydroxyanthranilic acid (3HAA), 5-hydroxyanthranilic acid (5HAA), and quinolinic acid (QA). However, 3HAA, 3HK, and QA at low concentrations may also serve as a precursor for nicotinamide adenine dinucleotide [NAD + ] which has vital importance to maintain cell viability. Inhibition of indoleamine 2,3-dioxygenase (IDO) activity results in a dosedependent decrease in intracellular [NAD + ] levels. Mitochondrial permeability transition occurs in several forms of necrotic cell death. Disturbances in the normal function of the mitochondria are associated with the alterations in the balance of Trp metabolism. While kynurenic acid (KA) has proven to be neuroprotective with the potential endogenous antioxidant properties, QA is a specifi c agonist at the N-methyl-d -aspartate (NMDA) receptors and a potent neurotoxin with the marked free radical-producing property. QA-induced cytotoxic effects are mediated by overactivation of NMDA-like receptors and overexpression of inducible nitric oxide synthase (iNOS). l -Kynurenine-derived neurotoxin-induced apoptosis occurs through reactive oxygen species (ROS)-mediated pathways and is blocked by antioxidants. Unlike the kynurenine pathway, the methoxyindole metabolites of Trp metabolism protect cells against oxidative stress-induced apoptosis. Furthermore, deprivation of Trp triggers autophagy in a mammalian target of rapamycin (mTOR)-dependent manner. mTOR inhibition can suppress the activation of cyclin-dependent kinases and then inhibits the cell cycle progress, suppresses cell proliferation, and fi nally results in cell apoptosis.

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“…mTOR, c-Jun, nuclear interacting partner of ALK (NIPA), and AKT) (13,18,19). It is highly possible that NPM-ALK induces serine/threonine phosphorylation of downstream targets through recruitment and activation of various serine/ threonine kinases like previously reported JNK and ERK (12,18).…”

Section: Molecular and Cellular Proteomics 9:1616 -1632 2010mentioning

confidence: 99%

“…NPM-ALK has been shown to have propensity to dimerize, and this process triggers autophosphorylation of NPM-ALK and results in constitutive activation of the ALK tyrosine kinase. Once activated, NPM-ALK binds, phosphorylates, and constitutively activates a host of proteins involved in various cellular signaling pathways, including those of PI3K/RAC-␣ serine/threonine-protein kinase (AKT) (8,9), JAK/STAT (10), mTOR (11)(12)(13), mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)/ERK (14), and Ras/ MAPK (15).…”

Section: Molecular and Cellular Proteomics 9:1616 -1632 2010mentioning

confidence: 99%

Studies of Phosphoproteomic Changes Induced by Nucleophosmin-Anaplastic Lymphoma Kinase (ALK) Highlight Deregulation of Tumor Necrosis Factor (TNF)/Fas/TNF-related Apoptosis-induced Ligand Signaling Pathway in ALK-positive Anaplastic Large Cell Lymphoma

Wang

Zhang

et al. 2010

Molecular & Cellular Proteomics

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The oncogenic fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), found exclusively in a subset of ALK-positive anaplastic large cell lymphoma, promotes tumorigenesis by exerting its constitutively active tyrosine kinase activity. Thus, characterization of the NPM-ALK-induced changes in the phosphoproteome will likely provide insights into the biology of this oncoprotein. To achieve this goal, we used a strategy of combining sequential affinity purification of phosphopeptides and LC/MS. GP293 cells transfected with either NPM-ALK or an NPM-ALK mutant with decreased tyrosine kinase activity (negative control) were used. We identified 506 phosphoproteins detectable in NPM-ALK-expressing cells but not in the negative control. Bioinformatics analysis revealed that these phosphoproteins carry a wide diversity of biological functions, some of which have not been described in association with NPM-ALK, such as the tumor necrosis factor (TNF)/Fas/tumor necrosis factorrelated apoptosis-induced ligand (TRAIL) signaling pathway and the ubiquitin proteasome degradation pathway. Anaplastic lymphoma kinase (ALK)1 -positive anaplastic large cell lymphoma (ALK ϩ ALCL) is a subtype of T/null cell non-Hodgkin lymphoma that is characterized by its consistent expression of CD30 and anaplastic cytology (1). ALK ϩ ALCL is relatively uncommon among adults, accounting for ϳ3% of adult non-Hodgkin lymphoma, whereas it is frequent in children, representing 10 -20% of all lymphoma (2). Approximately 80% of ALK ϩ ALCL tumors carry the t(2;5)(p23;q35) chromosomal translocation that fuses the tyrosine kinase doFrom the ‡Department

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Rapamycin reverses NPM-ALK-induced glucocorticoid resistance in lymphoid tumor cells by inhibiting mTOR signaling pathway, enhancing G1 cell cycle arrest and apoptosis

Cited by 39 publications

References 29 publications

Alcohol consumption and decreased risk of non-Hodgkin lymphoma: role of mTOR dysfunction

Alcohol consumption and decreased risk of non-Hodgkin lymphoma: role of mTOR dysfunction

Tryptophan and Cell Death

Studies of Phosphoproteomic Changes Induced by Nucleophosmin-Anaplastic Lymphoma Kinase (ALK) Highlight Deregulation of Tumor Necrosis Factor (TNF)/Fas/TNF-related Apoptosis-induced Ligand Signaling Pathway in ALK-positive Anaplastic Large Cell Lymphoma

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