title: MDM2 Inhibitor, Nutlin 3a, Induces p53 Dependent Autophagy in Acute Leukemia by AMP Kinase Activation.
abstract: 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.
authors.affiliation: Section of Molecular Hematology and Therapy; Departments of Leukemia and Stem Cell Transplantation, UT MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Gautam
authors.initials: G
authors.lastname: Borthakur
authors.affiliation: Section of Molecular Hematology and Therapy; Departments of Leukemia and Stem Cell Transplantation, UT MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Seshagiri
authors.initials: S
authors.lastname: Duvvuri
authors.affiliation: Section of Molecular Hematology and Therapy; Departments of Leukemia and Stem Cell Transplantation, UT MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Vivian
authors.initials: V
authors.lastname: Ruvolo
authors.affiliation: Centre for Translational Cancer Research, Institute for Biosciences & Technology, Texas A&M Health Science Center, Houston, Texas, United States of America.
authors.forename: Durga Nand
authors.initials: DN
authors.lastname: Tripathi
authors.affiliation: Section of Molecular Hematology and Therapy; Departments of Leukemia and Stem Cell Transplantation, UT MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Sujan
authors.initials: S
authors.lastname: Piya
authors.affiliation: Section of Molecular Hematology and Therapy; Departments of Leukemia and Stem Cell Transplantation, UT MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Jared
authors.initials: J
authors.lastname: Burks
authors.affiliation: Section of Molecular Hematology and Therapy; Departments of Leukemia and Stem Cell Transplantation, UT MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Jacamo
authors.affiliation: Section of Molecular Hematology and Therapy; Departments of Leukemia and Stem Cell Transplantation, UT MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kojima
authors.affiliation: Section of Molecular Hematology and Therapy; Departments of Leukemia and Stem Cell Transplantation, UT MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Ruvolo
authors.affiliation: Department of Neuro-oncology, UT MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Juan
authors.initials: J
authors.lastname: Fueyo-Margareto
authors.affiliation: Section of Molecular Hematology and Therapy; Departments of Leukemia and Stem Cell Transplantation, UT MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.affiliation: Section of Molecular Hematology and Therapy; Departments of Leukemia and Stem Cell Transplantation, UT MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D016086:Lentivirus / Q000235:genetics; D007938:Leukemia / Q000378:metabolism*; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D010879:Piperazines / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D007093:Imidazoles; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D051736:Proto-Oncogene Proteins c-mdm2; D000263:Adenylate Kinase