Oncogenic Stress Induced by Acute Hyper-Activation of Bcr-Abl Leads to Cell Death upon Induction of Excessive Aerobic Glycolysis
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{"title"=>"Oncogenic stress induced by acute hyper-activation of Bcr-Abl leads to cell death upon induction of excessive aerobic glycolysis", "type"=>"journal", "authors"=>[{"first_name"=>"Michael A.", "last_name"=>"Dengler", "scopus_author_id"=>"6602419822"}, {"first_name"=>"Annette M.", "last_name"=>"Staiger", "scopus_author_id"=>"54384332800"}, {"first_name"=>"Matthias", "last_name"=>"Gutekunst", "scopus_author_id"=>"35112329500"}, {"first_name"=>"Ute", "last_name"=>"Hofmann", "scopus_author_id"=>"7102885896"}, {"first_name"=>"Malgorzata", "last_name"=>"Doszczak", "scopus_author_id"=>"6506975593"}, {"first_name"=>"Peter", "last_name"=>"Scheurich", "scopus_author_id"=>"7006180484"}, {"first_name"=>"Matthias", "last_name"=>"Schwab", "scopus_author_id"=>"7201552009"}, {"first_name"=>"Walter E.", "last_name"=>"Aulitzky", "scopus_author_id"=>"26425472600"}, {"first_name"=>"Heiko", "last_name"=>"van der Kuip", "scopus_author_id"=>"35281271000"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"362585435", "sgr"=>"80052956828", "issn"=>"19326203", "pmid"=>"21949869", "scopus"=>"2-s2.0-80052956828", "doi"=>"10.1371/journal.pone.0025139", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)"}, "id"=>"8cda2a7b-9562-30a8-ac56-5852e4b02036", "abstract"=>"In response to deregulated oncogene activation, mammalian cells activate disposal programs such as programmed cell death. To investigate the mechanisms behind this oncogenic stress response we used Bcr-Abl over-expressing cells cultivated in presence of imatinib. Imatinib deprivation led to rapid induction of Bcr-Abl activity and over-stimulation of PI3K/Akt-, Ras/MAPK-, and JAK/STAT pathways. This resulted in a delayed necrosis-like cell death starting not before 48 hours after imatinib withdrawal. Cell death was preceded by enhanced glycolysis, glutaminolysis, and amino acid metabolism leading to elevated ATP and protein levels. This enhanced metabolism could be linked to induction of cell death as inhibition of glycolysis or glutaminolysis was sufficient to sustain cell viability. Therefore, these data provide first evidence that metabolic changes induced by Bcr-Abl hyper-activation are important mediators of oncogenic stress-induced cell death.During the first 30 hours after imatinib deprivation, Bcr-Abl hyper-activation did not affect proliferation but resulted in cellular swelling, vacuolization, and induction of eIF2α phosphorylation, CHOP expression, as well as alternative splicing of XPB, indicating endoplasmic reticulum stress response. Cell death was dependent on p38 and RIP1 signaling, whereas classical death effectors of ER stress, namely CHOP-BIM were antagonized by concomitant up-regulation of Bcl-xL.Screening of 1,120 compounds for their potential effects on oncogenic stress-induced cell death uncovered that corticosteroids antagonize cell death upon Bcr-Abl hyper-activation by normalizing cellular metabolism. This protective effect is further demonstrated by the finding that corticosteroids rendered lymphocytes permissive to the transforming activity of Bcr-Abl. As corticosteroids are used together with imatinib for treatment of Bcr-Abl positive acute lymphoblastic leukemia these data could have important implications for the design of combination therapy protocols.In conclusion, excessive induction of Warburg type metabolic alterations can cause cell death. Our data indicate that these metabolic changes are major mediators of oncogenic stress induced by Bcr-Abl.", "link"=>"http://www.mendeley.com/research/oncogenic-stress-induced-acute-hyperactivation-bcrabl-leads-cell-death-upon-induction-excessive-aero", "reader_count"=>50, "reader_count_by_academic_status"=>{"Unspecified"=>4, "Professor > Associate Professor"=>3, "Researcher"=>11, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>2, "Student > Master"=>10, "Other"=>1, "Student > Bachelor"=>1, "Professor"=>4}, "reader_count_by_user_role"=>{"Unspecified"=>4, "Professor > Associate Professor"=>3, "Researcher"=>11, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>2, "Student > Master"=>10, "Other"=>1, "Student > Bachelor"=>1, "Professor"=>4}, "reader_count_by_subject_area"=>{"Unspecified"=>7, "Engineering"=>2, "Biochemistry, Genetics and Molecular Biology"=>6, "Agricultural and Biological Sciences"=>23, "Medicine and Dentistry"=>7, "Neuroscience"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Chemistry"=>1, "Immunology and Microbiology"=>2}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>2}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>7}, "Neuroscience"=>{"Neuroscience"=>1}, "Chemistry"=>{"Chemistry"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>23}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>6}, "Unspecified"=>{"Unspecified"=>7}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Czech Republic"=>1, "United States"=>1, "Brazil"=>1, "Germany"=>1}, "group_count"=>4}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/734021"], "description"=>"<p>(A) Colony number and colony size of BaF3 cells transfected with an expression vector containing e1a2<i>bcr-abl</i> as insert in presence or absence of prednisolone or betamethasone. 48 hours after transfection cells were counted and further cultivated in semisolid medium with or without prednisolone or bethamethasone. Left panel: photographs of representative wells (from 6-well plates). Right panel: colony numbers of cells transfected in absence (c) or presence of prednisolone (p; **: <i>P</i> = 0.0013) or betamethasone (b; **: <i>P</i> = 0.0013). Values reflect means ± SEM of triplicates from 3 independent experiments (B) Bcr-Abl expression and autophosphorylation of <i>bcr-abl</i> transfected cell clones. Left panel: representative example. Right panels: relative Bcr-Abl protein levels in absence (c) or presence of prednisolone (p) or betamethasone (b) and relative autophosphorylation in absence (c) or presence of prednisolone (p; *: <i>P</i> = 0.0126) or betamethasone (b; *: <i>P</i> = 0.0364) were measured by forming the ratio of the densitometric values of bands pooled from results of 10 clones.</p>", "links"=>[], "tags"=>["baf3", "cells", "permissive", "transforming"], "article_id"=>404365, "categories"=>["Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Michael A. Dengler", "Annette M. Staiger", "Matthias Gutekunst", "Ute Hofmann", "Malgorzata Doszczak", "Peter Scheurich", "Matthias Schwab", "Walter E. Aulitzky", "Heiko van der Kuip"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025139.g006", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Corticosteroids_render_the_BaF3_cells_permissive_for_the_transforming_activity_of_Bcr_Abl_/404365", "title"=>"Corticosteroids render the BaF3 cells permissive for the transforming activity of Bcr-Abl.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-20 01:12:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/733838"], "description"=>"<p>(A) Effects of a panel of 1,120 approved small molecule inhibitors (Prestwick library) on cell survival upon imatinib-deprivation. Cells were incubated with DMSO control, inhibitors and with or without imatinib for 48 hours and cell survival was then measured by MTT colorimetric analysis. Values reflect percent survival of cells treated with inhibitor in absence of imatinib in relation to imatinib treated controls. Survival of imatinib withdrawal alone is indicated by a dotted line. (B) Effects of betamethasone (**: <i>P</i> = 0.001) and prednisolone (***: <i>P</i><0.0001) on induction of cell death (left panel) and glucose metabolism (right panel) on imatinib withdrawal induced cell death. Cells were cultivated in the presence or absence of betamethasone, prednisolone, and imatinib for 48 hours and then harvested for cell death quantification by Annexin V staining and flow cytometry (left panel) or for fixation and preparation for GC-MS or LC-MS-MS (right panel). Values reflect means ± SD from 3 experiments.</p>", "links"=>[], "tags"=>["altered", "metabolism", "induced", "imatinib", "imr"], "article_id"=>404179, "categories"=>["Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Michael A. Dengler", "Annette M. Staiger", "Matthias Gutekunst", "Ute Hofmann", "Malgorzata Doszczak", "Peter Scheurich", "Matthias Schwab", "Walter E. Aulitzky", "Heiko van der Kuip"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025139.g005", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Modulation_of_cell_death_and_altered_metabolism_induced_by_imatinib_withdrawal_in_IMR_cells_/404179", "title"=>"Modulation of cell death and altered metabolism induced by imatinib withdrawal in IMR cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-20 01:09:39"}
  • {"files"=>["https://ndownloader.figshare.com/files/733256"], "description"=>"<p>(A) Bcr-Abl expression and activity. Upper panel: Bcr-Abl protein level and autophosphorylation in imatinib-sensitive cells (p190wt) in comparison to imatinib-resistant cell clones (IMR6 and IMR10) in the presence or absence of 2 µM imatinib. Lower panel: activity of Bcr-Abl downstream-signaling in IMR cells in the presence of imatinib and following imatinib withdrawal. (B) Effect of imatinib on survival (as measured by MTT) of Bcr-Abl over-expressing p190IMR clones in comparison to cell expressing wtBcr-Abl (p190wt) or T315IBcr-Abl (p190T315I). IC50 values of p190wt and p190T315I cells are indicated with dotted lines (C) Effect of imatinib deprivation on cell cycle distribution. Cells were cultivated in absence or presence of imatinib for indicated time periods and pulse treated with BrdU for 45 min. Cells were then fixed and evaluated for DNA content and synthesis via BrdU and propidium iodide (PI) staining and analyzed by flow cytometry. (D) Effect of imatinib deprivation on cell viability. Cells were stained with Annexin V or PI alone (upper two panels) or with the combination of both Annexin V and PI (lower panel) and analyzed by Flow cytometry.</p>", "links"=>[], "tags"=>["bcr-abl", "over-expressing", "imatinib", "resistant"], "article_id"=>403601, "categories"=>["Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Michael A. Dengler", "Annette M. Staiger", "Matthias Gutekunst", "Ute Hofmann", "Malgorzata Doszczak", "Peter Scheurich", "Matthias Schwab", "Walter E. Aulitzky", "Heiko van der Kuip"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025139.g001", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Phenotype_of_Bcr_Abl_over_expressing_imatinib_resistant_IMR_cells_/403601", "title"=>"Phenotype of Bcr-Abl over-expressing imatinib resistant (IMR) cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-20 01:00:01"}
  • {"files"=>["https://ndownloader.figshare.com/files/734114"], "description"=>"<p>siRNA target sequences.</p>", "links"=>[], "tags"=>["molecular biology", "cell biology", "oncology"], "article_id"=>404464, "categories"=>["Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Michael A. Dengler", "Annette M. Staiger", "Matthias Gutekunst", "Ute Hofmann", "Malgorzata Doszczak", "Peter Scheurich", "Matthias Schwab", "Walter E. Aulitzky", "Heiko van der Kuip"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025139.t001", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_siRNA_target_sequences_/404464", "title"=>"siRNA target sequences.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-09-20 01:14:24"}
  • {"files"=>["https://ndownloader.figshare.com/files/733585"], "description"=>"<p>(A) Phase contrast images of IMR cells cultivated with or without imatinib for 24 hours (left panels) and p190IMR cells stained with ER-TrackerTMGreen dye (Invitrogen) 24 hours after imatinib withdrawal (right panel). (B) Imatinib withdrawal induces prototypical ER stress markers. Left panel: phosphorylation of eIF2α and protein level of CHOP in presence of imatinib and upon imatinib withdrawal evaluated after indicated time periods by western blot analysis. Right panel: agarose gel electrophoresis of <i>XBP-1</i> splicing variants amplified by PCR.</p>", "links"=>[], "tags"=>["induces", "er"], "article_id"=>403933, "categories"=>["Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Michael A. Dengler", "Annette M. Staiger", "Matthias Gutekunst", "Ute Hofmann", "Malgorzata Doszczak", "Peter Scheurich", "Matthias Schwab", "Walter E. Aulitzky", "Heiko van der Kuip"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025139.g003", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Imatinib_withdrawal_induces_ER_stress_/403933", "title"=>"Imatinib withdrawal induces ER stress.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-20 01:05:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/733453"], "description"=>"<p>(A) ATP content (*: <i>P</i> = 0.0313, left panel), protein content (*: <i>P</i> = 0.0367, middle panel), and cell size (***: <i>P</i><0.0001, right panel) of IMR cells cultivated with imatinib or 24 hours after imatinib withdrawal. Values reflect means ± SD from 3 experiments. (B) Effects of imatinib withdrawal on glucose and amino acid metabolism. Cells were cultivated in presence or absence of imatinib for 24 hours and then harvested and prepared for GC-MS or LC-MS-MS. Values reflect means ± SD from 3 experiments. (C) Induction of cell death in IMR cells cultivated with imatinib or 48 hours after imatinib withdrawal in the presence or absence of 2-deoxy-D-glucose (**: <i>P</i> = 0.0048, upper panel), in medium with different glutamine concentrations (*: <i>P</i> = 0.02, middle panel) or in presence or absence of 6-diazo-5-oxo-l-norleucine (DON; **: <i>P</i> = 0.0014). After treatment cells were harvested, stained for Annexin-V-FITC and cell death was quantified by FACS analysis. Values reflect means ± SD from 3 experiments.</p>", "links"=>[], "tags"=>["alters", "metabolism", "imr"], "article_id"=>403798, "categories"=>["Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Michael A. Dengler", "Annette M. Staiger", "Matthias Gutekunst", "Ute Hofmann", "Malgorzata Doszczak", "Peter Scheurich", "Matthias Schwab", "Walter E. Aulitzky", "Heiko van der Kuip"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025139.g002", "stats"=>{"downloads"=>4, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Imatinib_withdrawal_alters_cell_metabolism_in_IMR_cells_/403798", "title"=>"Imatinib withdrawal alters cell metabolism in IMR cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-20 01:03:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/370381", "https://ndownloader.figshare.com/files/370444", "https://ndownloader.figshare.com/files/370493", "https://ndownloader.figshare.com/files/370538", "https://ndownloader.figshare.com/files/370580", "https://ndownloader.figshare.com/files/370640"], "description"=>"<div><p>In response to deregulated oncogene activation, mammalian cells activate disposal programs such as programmed cell death. To investigate the mechanisms behind this oncogenic stress response we used Bcr-Abl over-expressing cells cultivated in presence of imatinib. Imatinib deprivation led to rapid induction of Bcr-Abl activity and over-stimulation of PI3K/Akt-, Ras/MAPK-, and JAK/STAT pathways. This resulted in a delayed necrosis-like cell death starting not before 48 hours after imatinib withdrawal. Cell death was preceded by enhanced glycolysis, glutaminolysis, and amino acid metabolism leading to elevated ATP and protein levels. This enhanced metabolism could be linked to induction of cell death as inhibition of glycolysis or glutaminolysis was sufficient to sustain cell viability. Therefore, these data provide first evidence that metabolic changes induced by Bcr-Abl hyper-activation are important mediators of oncogenic stress-induced cell death.</p> <p>During the first 30 hours after imatinib deprivation, Bcr-Abl hyper-activation did not affect proliferation but resulted in cellular swelling, vacuolization, and induction of eIF2α phosphorylation, CHOP expression, as well as alternative splicing of <em>XPB</em>, indicating endoplasmic reticulum stress response. Cell death was dependent on p38 and RIP1 signaling, whereas classical death effectors of ER stress, namely CHOP-BIM were antagonized by concomitant up-regulation of Bcl-xL.</p> <p>Screening of 1,120 compounds for their potential effects on oncogenic stress-induced cell death uncovered that corticosteroids antagonize cell death upon Bcr-Abl hyper-activation by normalizing cellular metabolism. This protective effect is further demonstrated by the finding that corticosteroids rendered lymphocytes permissive to the transforming activity of Bcr-Abl. As corticosteroids are used together with imatinib for treatment of Bcr-Abl positive acute lymphoblastic leukemia these data could have important implications for the design of combination therapy protocols.</p> <p>In conclusion, excessive induction of Warburg type metabolic alterations can cause cell death. Our data indicate that these metabolic changes are major mediators of oncogenic stress induced by Bcr-Abl.</p> </div>", "links"=>[], "tags"=>["oncogenic", "induced", "acute", "hyper-activation", "bcr-abl", "leads", "induction", "aerobic", "glycolysis"], "article_id"=>133171, "categories"=>["Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Michael A. Dengler", "Annette M. Staiger", "Matthias Gutekunst", "Ute Hofmann", "Malgorzata Doszczak", "Peter Scheurich", "Matthias Schwab", "Walter E. Aulitzky", "Heiko van der Kuip"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0025139.s001", "https://dx.doi.org/10.1371/journal.pone.0025139.s002", "https://dx.doi.org/10.1371/journal.pone.0025139.s003", "https://dx.doi.org/10.1371/journal.pone.0025139.s004", "https://dx.doi.org/10.1371/journal.pone.0025139.s005", "https://dx.doi.org/10.1371/journal.pone.0025139.s006"], "stats"=>{"downloads"=>5, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Oncogenic_Stress_Induced_by_Acute_Hyper_Activation_of_Bcr_Abl_Leads_to_Cell_Death_upon_Induction_of_Excessive_Aerobic_Glycolysis/133171", "title"=>"Oncogenic Stress Induced by Acute Hyper-Activation of Bcr-Abl Leads to Cell Death upon Induction of Excessive Aerobic Glycolysis", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2011-09-20 00:52:51"}
  • {"files"=>["https://ndownloader.figshare.com/files/733718"], "description"=>"<p>(A) BIM is highly induced but does not affect cell death upon imatinib deprivation. Left panel: Cells were cultivated in presence or absence of imatinib for indicated time periods and harvested for detection of BIM protein variants in western blot analysis. Right panel: cells were transfected with control siRNA or siRNA targeting BIM or CHOP. After 16 hours medium was changed and cells were further cultivated with or without imatinib for 48 hours. Cells were then harvested for western blot analysis or quantification of cell death by Annexin staining and flow cytometry. (B) Apoptosis is antagonized by a parallel induction of Bcl-xL. Upper panel: western blot analysis of Bcl-xL from cells cultivated with or without imatinib. Lower panel: inhibition of Bcl-xL by ABT-737 leads to induction of apoptosis early after imatinib withdrawal (***: <i>P</i> = 0.0012). Cells were cultivated in the presence and absence of imatinib and ABT-737 for 24 hours and then harvested for Annexin V-FITC staining and flow cytometry. Values reflect means ± SD from 3 experiments. (C) RIP1 and p38 activity is induced upon imatinib withdrawal and responsive for induction of cell death. Left panel: cells were cultivated with or without imatinib and harvested for western blot analysis using specific antibodies recognizing p38-Thr180/Tyr182, p38 or RIP1. Right panel: inhibition of RIP1 by Necrostatin-1 (**: <i>P</i> = 0.0076) and inhibition of p38 (*: <i>P</i> = 0.0102) antagonize cell death upon imatinib withdrawal. Cells were incubated with or without Necrostatin-1 and p38 inhibitor III and imatinib for 48 hours and then harvested for Annexin V staining and flow cytometry. Values reflect means ± SD from 3 experiments. (D) Inhibition of glycolysis or p38 activity abrogates RIP1 posttranslational modification upon Imatinib withdrawal. Cells were incubated with or without 2-deoxy-D-glucose or p38 inhibitor III and Imatinib as indicated. 48 hours after Imatinib withdrawal cells were harvested for western blot analysis.</p>", "links"=>[], "tags"=>["deprivation", "leads", "non-apoptotic", "mediated", "p38"], "article_id"=>404065, "categories"=>["Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Michael A. Dengler", "Annette M. Staiger", "Matthias Gutekunst", "Ute Hofmann", "Malgorzata Doszczak", "Peter Scheurich", "Matthias Schwab", "Walter E. Aulitzky", "Heiko van der Kuip"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025139.g004", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Imatinib_deprivation_leads_to_non_apoptotic_cell_death_mediated_by_p38_and_RIP1_/404065", "title"=>"Imatinib deprivation leads to non-apoptotic cell death mediated by p38 and RIP1.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-20 01:07:45"}

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Relative Metric

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