Aurora A and NF-κB Survival Pathway Drive Chemoresistance in Acute Myeloid Leukemia via the TRAF-Interacting Protein TIFA

• Published in: Cancer research (Chicago, Ill.) Vol. 77; no. 2; pp. 494 - 508
• Main Authors: Wei, Tong-You Wade, Wu, Pei-Yu, Wu, Ting-Jung, Hou, Hsin-An, Chou, Wen-Chien, Teng, Chieh-Lin Jerry, Lin, Chih-Ru, Chen, Jo-Mei Maureen, Lin, Ting-Yang, Su, Hsiang-Chun, Huang, Chia-Chi Flora, Yu, Chang-Tze Ricky, Hsu, Shih-Lan, Tien, Hwei-Fang, Tsai, Ming-Daw
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research, Inc 15.01.2017
• Subjects: Acute myeloid leukemia; Adaptor Proteins, Signal Transducing - metabolism; Animals; Apoptosis; Aurora Kinase A - metabolism; Bcl-2 protein; Bcl-x protein; Blotting, Western; Bone marrow; Cancer; Cell Line, Tumor; Chemoresistance; Disease Progression; Disease-Free Survival; Drug Resistance, Neoplasm - physiology; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Fluorescent Antibody Technique; Gene Knockdown Techniques; Heterografts; Humans; Immunoprecipitation; Kaplan-Meier Estimate; Leukemia; Leukemia, Myeloid, Acute - mortality; Leukemia, Myeloid, Acute - pathology; Medical prognosis; Mice; Myeloid leukemia; NF-kappa B - metabolism; NF-κB protein; Phosphorylation; Prognosis; Proportional Hazards Models; Proteins; Rodents; Signal transduction; Signal Transduction - physiology; Xenografts
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-16-1004

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-XL that support NF-κB–dependent antiapoptotic events. Inhibiting TIFA perturbed leukemic cytokine secretion and reduced the IC50 of 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.