TY - JOUR
T1 - MDM2 inhibitor, Nutlin 3a, induces p53 dependent autophagy in acute leukemia by AMP kinase activation
AU - Borthakur, Gautam
AU - Duvvuri, Seshagiri
AU - Ruvolo, Vivian
AU - Tripathi, Durga Nand
AU - Piya, Sujan
AU - Burks, Jared
AU - Jacamo, Rodrigo
AU - Kojima, Kensuke
AU - Ruvolo, Peter
AU - Fueyo-Margareto, Juan
AU - Konopleva, Marina
AU - Andreeff, Michael
N1 - Publisher Copyright:
© 2015 Borthakur et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2015/10/6
Y1 - 2015/10/6
N2 - 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 nontranscriptionally. 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 proapoptotic as pharmacological (bafilomycin) or genetic inhibition (BECLIN1 knockdown) of autophagy impairs apoptosis induced by Nutlin 3a.
AB - 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 nontranscriptionally. 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 proapoptotic as pharmacological (bafilomycin) or genetic inhibition (BECLIN1 knockdown) of autophagy impairs apoptosis induced by Nutlin 3a.
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U2 - 10.1371/journal.pone.0139254
DO - 10.1371/journal.pone.0139254
M3 - Article
C2 - 26440941
AN - SCOPUS:84947968556
SN - 1932-6203
VL - 10
JO - PloS one
JF - PloS one
IS - 10
M1 - e0139254
ER -