MDM2 Inhibitor, Nutlin 3a, Induces p53 Dependent Autophagy in Acute Leukemia by AMP Kinase Activation.

MDM2 Inhibitor, Nutlin 3a, Induces p53 Dependent Autophagy in Acute Leukemia by AMP Kinase Activation.

MDM2 (mouse double minute 2) inhibitors that activate p53 and induce apoptosis in a non-genotoxic manner are in clinical development for treatment of leukemias. P53 can modulate other programmed cell death pathways including autophagy both transcriptionally and non-transcriptionally. We investigated...

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Main Authors: Gautam Borthakur, Seshagiri Duvvuri, Vivian Ruvolo, Durga Nand Tripathi, Sujan Piya, Jared Burks, Rodrigo Jacamo, Kensuke Kojima, Peter Ruvolo, Juan Fueyo-Margareto, Marina Konopleva, Michael Andreeff
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2015-01-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC4595506?pdf=render
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spelling doaj-1e29b2e8f776433bb52a37ec5080a36e2020-11-25T02:36:43ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-011010e013925410.1371/journal.pone.0139254MDM2 Inhibitor, Nutlin 3a, Induces p53 Dependent Autophagy in Acute Leukemia by AMP Kinase Activation.Gautam BorthakurSeshagiri DuvvuriVivian RuvoloDurga Nand TripathiSujan PiyaJared BurksRodrigo JacamoKensuke KojimaPeter RuvoloJuan Fueyo-MargaretoMarina KonoplevaMichael AndreeffMDM2 (mouse double minute 2) inhibitors that activate p53 and induce apoptosis in a non-genotoxic manner are in clinical development for treatment of leukemias. P53 can modulate other programmed cell death pathways including autophagy both transcriptionally and non-transcriptionally. We investigated autophagy induction in acute leukemia by Nutlin 3a, a first-in-class MDM2 inhibitor. Nutlin 3a induced autophagy in a p53 dependent manner and transcriptional activation of AMP kinase (AMPK) is critical, as this effect is abrogated in AMPK -/- mouse embryonic fibroblasts. Nutlin 3a induced autophagy appears to be pro-apoptotic as pharmacological (bafilomycin) or genetic inhibition (BECLIN1 knockdown) of autophagy impairs apoptosis induced by Nutlin 3a.http://europepmc.org/articles/PMC4595506?pdf=render
collection DOAJ
language English
format Article
sources DOAJ
author Gautam Borthakur
Seshagiri Duvvuri
Vivian Ruvolo
Durga Nand Tripathi
Sujan Piya
Jared Burks
Rodrigo Jacamo
Kensuke Kojima
Peter Ruvolo
Juan Fueyo-Margareto
Marina Konopleva
Michael Andreeff
spellingShingle Gautam Borthakur
Seshagiri Duvvuri
Vivian Ruvolo
Durga Nand Tripathi
Sujan Piya
Jared Burks
Rodrigo Jacamo
Kensuke Kojima
Peter Ruvolo
Juan Fueyo-Margareto
Marina Konopleva
Michael Andreeff
MDM2 Inhibitor, Nutlin 3a, Induces p53 Dependent Autophagy in Acute Leukemia by AMP Kinase Activation.
PLoS ONE
author_facet Gautam Borthakur
Seshagiri Duvvuri
Vivian Ruvolo
Durga Nand Tripathi
Sujan Piya
Jared Burks
Rodrigo Jacamo
Kensuke Kojima
Peter Ruvolo
Juan Fueyo-Margareto
Marina Konopleva
Michael Andreeff
author_sort Gautam Borthakur
title MDM2 Inhibitor, Nutlin 3a, Induces p53 Dependent Autophagy in Acute Leukemia by AMP Kinase Activation.
title_short MDM2 Inhibitor, Nutlin 3a, Induces p53 Dependent Autophagy in Acute Leukemia by AMP Kinase Activation.
title_full MDM2 Inhibitor, Nutlin 3a, Induces p53 Dependent Autophagy in Acute Leukemia by AMP Kinase Activation.
title_fullStr MDM2 Inhibitor, Nutlin 3a, Induces p53 Dependent Autophagy in Acute Leukemia by AMP Kinase Activation.
title_full_unstemmed MDM2 Inhibitor, Nutlin 3a, Induces p53 Dependent Autophagy in Acute Leukemia by AMP Kinase Activation.
title_sort mdm2 inhibitor, nutlin 3a, induces p53 dependent autophagy in acute leukemia by amp kinase activation.
publisher Public Library of Science (PLoS)
series PLoS ONE
issn 1932-6203
publishDate 2015-01-01
description MDM2 (mouse double minute 2) inhibitors that activate p53 and induce apoptosis in a non-genotoxic manner are in clinical development for treatment of leukemias. P53 can modulate other programmed cell death pathways including autophagy both transcriptionally and non-transcriptionally. We investigated autophagy induction in acute leukemia by Nutlin 3a, a first-in-class MDM2 inhibitor. Nutlin 3a induced autophagy in a p53 dependent manner and transcriptional activation of AMP kinase (AMPK) is critical, as this effect is abrogated in AMPK -/- mouse embryonic fibroblasts. Nutlin 3a induced autophagy appears to be pro-apoptotic as pharmacological (bafilomycin) or genetic inhibition (BECLIN1 knockdown) of autophagy impairs apoptosis induced by Nutlin 3a.
url http://europepmc.org/articles/PMC4595506?pdf=render
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