Oncogenic stress induced by acute hyper-activation of Bcr-Abl leads to cell death upon induction of excessive aerobic glycolysis.

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 in...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Michael A Dengler, Annette M Staiger, Matthias Gutekunst, Ute Hofmann, Malgorzata Doszczak, Peter Scheurich, Matthias Schwab, Walter E Aulitzky, Heiko van der Kuip
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/30003634020a4e90af9989fc1b2c9212
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:30003634020a4e90af9989fc1b2c9212
record_format	dspace
spelling	oai:doaj.org-article:30003634020a4e90af9989fc1b2c92122021-11-04T06:08:10ZOncogenic stress induced by acute hyper-activation of Bcr-Abl leads to cell death upon induction of excessive aerobic glycolysis.1932-620310.1371/journal.pone.0025139https://doaj.org/article/30003634020a4e90af9989fc1b2c92122011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21949869/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203In 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.Michael A DenglerAnnette M StaigerMatthias GutekunstUte HofmannMalgorzata DoszczakPeter ScheurichMatthias SchwabWalter E AulitzkyHeiko van der KuipPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 9, p e25139 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Michael A Dengler Annette M Staiger Matthias Gutekunst Ute Hofmann Malgorzata Doszczak Peter Scheurich Matthias Schwab Walter E Aulitzky Heiko van der Kuip Oncogenic stress induced by acute hyper-activation of Bcr-Abl leads to cell death upon induction of excessive aerobic glycolysis.
description	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.
format	article
author	Michael A Dengler Annette M Staiger Matthias Gutekunst Ute Hofmann Malgorzata Doszczak Peter Scheurich Matthias Schwab Walter E Aulitzky Heiko van der Kuip
author_facet	Michael A Dengler Annette M Staiger Matthias Gutekunst Ute Hofmann Malgorzata Doszczak Peter Scheurich Matthias Schwab Walter E Aulitzky Heiko van der Kuip
author_sort	Michael A Dengler
title	Oncogenic stress induced by acute hyper-activation of Bcr-Abl leads to cell death upon induction of excessive aerobic glycolysis.
title_short	Oncogenic stress induced by acute hyper-activation of Bcr-Abl leads to cell death upon induction of excessive aerobic glycolysis.
title_full	Oncogenic stress induced by acute hyper-activation of Bcr-Abl leads to cell death upon induction of excessive aerobic glycolysis.
title_fullStr	Oncogenic stress induced by acute hyper-activation of Bcr-Abl leads to cell death upon induction of excessive aerobic glycolysis.
title_full_unstemmed	Oncogenic stress induced by acute hyper-activation of Bcr-Abl leads to cell death upon induction of excessive aerobic glycolysis.
title_sort	oncogenic stress induced by acute hyper-activation of bcr-abl leads to cell death upon induction of excessive aerobic glycolysis.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/30003634020a4e90af9989fc1b2c9212
work_keys_str_mv	AT michaeladengler oncogenicstressinducedbyacutehyperactivationofbcrablleadstocelldeathuponinductionofexcessiveaerobicglycolysis AT annettemstaiger oncogenicstressinducedbyacutehyperactivationofbcrablleadstocelldeathuponinductionofexcessiveaerobicglycolysis AT matthiasgutekunst oncogenicstressinducedbyacutehyperactivationofbcrablleadstocelldeathuponinductionofexcessiveaerobicglycolysis AT utehofmann oncogenicstressinducedbyacutehyperactivationofbcrablleadstocelldeathuponinductionofexcessiveaerobicglycolysis AT malgorzatadoszczak oncogenicstressinducedbyacutehyperactivationofbcrablleadstocelldeathuponinductionofexcessiveaerobicglycolysis AT peterscheurich oncogenicstressinducedbyacutehyperactivationofbcrablleadstocelldeathuponinductionofexcessiveaerobicglycolysis AT matthiasschwab oncogenicstressinducedbyacutehyperactivationofbcrablleadstocelldeathuponinductionofexcessiveaerobicglycolysis AT waltereaulitzky oncogenicstressinducedbyacutehyperactivationofbcrablleadstocelldeathuponinductionofexcessiveaerobicglycolysis AT heikovanderkuip oncogenicstressinducedbyacutehyperactivationofbcrablleadstocelldeathuponinductionofexcessiveaerobicglycolysis
_version_	1718445141539160064

Oncogenic stress induced by acute hyper-activation of Bcr-Abl leads to cell death upon induction of excessive aerobic glycolysis.

Ejemplares similares