title: Direct binding of arsenic trioxide to AMPK and generation of inhibitory effects on acute myeloid leukemia precursors.
abstract: Arsenic trioxide (As2O3) exhibits potent antineoplastic effects and is used extensively in clinical oncology for the treatment of a subset of patients with acute myeloid leukemia (AML). Although As2O3 is known to regulate activation of several signaling cascades, the key events, accounting for its antileukemic properties, remain to be defined. We provide evidence that arsenic can directly bind to cysteine 299 in AMPKα and inhibit its activity. This inhibition of AMPK by arsenic is required in part for its cytotoxic effects on primitive leukemic progenitors from patients with AML, while concomitant treatment with an AMPK activator antagonizes in vivo the arsenic-induced antileukemic effects in a xenograft AML mouse model. A consequence of AMPK inhibition is activation of the mTOR pathway as a negative regulatory feedback loop. However, when AMPK expression is lost, arsenic-dependent activation of the kinase RSK downstream of MAPK activity compensates the generation of regulatory feedback signals through phosphorylation of downstream mTOR targets. Thus, therapeutic regimens with As2O3 will need to include inhibitors of both the mTOR and RSK pathways in combination to prevent engagement of negative feedback loops and maximize antineoplastic responses.
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois. Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Division of Hematology-Oncology, Department of Medicine, Jesse Brown VA Medical Center, Chicago, Illinois.
authors.forename: Elspeth M
authors.initials: EM
authors.lastname: Beauchamp
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois. Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Ewa M
authors.initials: EM
authors.lastname: Kosciuczuk
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois. Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Ruth
authors.initials: R
authors.lastname: Serrano
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois.
authors.forename: Dhaval
authors.initials: D
authors.lastname: Nanavati
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois. Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois. Department of Chemical and Biological Engineering, Northwestern University, Evanston, Illinois.
authors.forename: Elden P
authors.initials: EP
authors.lastname: Swindell
authors.affiliation: Institut Cochin, Université Paris Descartes, CNRs (UMR8104) and INSERM U1016, Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois. Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois. Department of Chemistry, Northwestern University, Evanston, Illinois.
authors.forename: Thomas V
authors.initials: TV
authors.lastname: O'Halloran
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois. Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Division of Hematology-Oncology, Department of Medicine, Jesse Brown VA Medical Center, Chicago, Illinois.
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Altman
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois. Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Division of Hematology-Oncology, Department of Medicine, Jesse Brown VA Medical Center, Chicago, Illinois. l-platanias@northwestern.edu.
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D010087:Oxides / Q000494:pharmacology*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000077237:Arsenic Trioxide