title: Aurora A and NF-κB Survival Pathway Drive Chemoresistance in Acute Myeloid Leukemia via the TRAF-Interacting Protein TIFA.
abstract: Aurora A-dependent NF-κB signaling portends poor prognosis in acute myeloid leukemia (AML) and other cancers, but the functional basis underlying this association is unclear. Here, we report that Aurora A is essential for Thr9 phosphorylation of the TRAF-interacting protein TIFA, triggering activation of the NF-κB survival pathway in AML. TIFA protein was overexpressed concurrently with Aurora A and NF-κB signaling factors in patients with de novo AML relative to healthy individuals and also correlated with poor prognosis. Silencing TIFA in AML lines and primary patient cells decreased leukemic cell growth and chemoresistance via downregulation of prosurvival factors Bcl-2 and Bcl-XLthat support NF-κB-dependent antiapoptotic events. Inhibiting TIFA perturbed leukemic cytokine secretion and reduced the IC50of chemotherapeutic drug treatments in AML cells. Furthermore, in vivo delivery of TIFA-inhibitory fragments potentiated the clearance of myeloblasts in the bone marrow of xenograft-recipient mice via enhanced chemotoxicity. Collectively, our results showed that TIFA supports AML progression and that its targeting can enhance the efficacy of AML treatments. Cancer Res; 77(2); 494-508. ©2016 AACR.
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.|Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.
authors.forename: Tong-You Wade
authors.initials: TW
authors.lastname: Wei
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Pei-Yu
authors.initials: PY
authors.lastname: Wu
authors.affiliation: Division of Liver and Transplantation Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan. mdtsai@gate.sinica.edu.tw wutj5056@cgmh.org.tw hsinanhou@ntu.edu.tw.
authors.forename: Ting-Jung
authors.initials: TJ
authors.lastname: Wu
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. mdtsai@gate.sinica.edu.tw wutj5056@cgmh.org.tw hsinanhou@ntu.edu.tw.
authors.forename: Hsin-An
authors.initials: HA
authors.lastname: Hou
authors.affiliation: Departments of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Wen-Chien
authors.initials: WC
authors.lastname: Chou
authors.affiliation: Division of Hematology/Medical Oncology, Department of Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Chieh-Lin Jerry
authors.initials: CJ
authors.lastname: Teng
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.|Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.
authors.forename: Chih-Ru
authors.initials: CR
authors.lastname: Lin
authors.affiliation: Department of Applied Chemistry, National Chi Nan University, Nantou, Taiwan.
authors.forename: Jo-Mei Maureen
authors.initials: JM
authors.lastname: Chen
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.|Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.
authors.forename: Ting-Yang
authors.initials: TY
authors.lastname: Lin
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.|Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.
authors.forename: Hsiang-Chun
authors.initials: HC
authors.lastname: Su
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Chia-Chi Flora
authors.initials: CF
authors.lastname: Huang
authors.affiliation: Department of Applied Chemistry, National Chi Nan University, Nantou, Taiwan.
authors.forename: Chang-Tze Ricky
authors.initials: CR
authors.lastname: Yu
authors.affiliation: Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Shih-Lan
authors.initials: SL
authors.lastname: Hsu
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Hwei-Fang
authors.initials: HF
authors.lastname: Tien
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan. mdtsai@gate.sinica.edu.tw wutj5056@cgmh.org.tw hsinanhou@ntu.edu.tw.|Genomics Research Center, Academia Sinica, Taipei, Taiwan.|Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.
authors.forename: Ming-Daw
authors.initials: MD
authors.lastname: Tsai
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D064096:Aurora Kinase A / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D018450:Disease Progression; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D047468:Immunoprecipitation; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000401:mortality / Q000473:pathology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D016016:Proportional Hazards Models; D015398:Signal Transduction / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016328:NF-kappa B; C446759:TIFA protein, human; C576917:AURKA protein, human; D064096:Aurora Kinase A