title: TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT.
abstract: Intrinsic and acquired resistance to chemotherapy is the fundamental reason for treatment failure for many cancer patients. The identification of molecular mechanisms involved in drug resistance or sensitization is imperative. Here we report that tribbles homologue 2 (TRIB2) ablates forkhead box O activation and disrupts the p53/MDM2 regulatory axis, conferring resistance to various chemotherapeutics. TRIB2 suppression is exerted via direct interaction with AKT a key signalling protein in cell proliferation, survival and metabolism pathways. Ectopic or intrinsic high expression of TRIB2 induces drug resistance by promoting phospho-AKT (at Ser473) via its COP1 domain. TRIB2 expression is significantly increased in tumour tissues from patients correlating with an increased phosphorylation of AKT, FOXO3a, MDM2 and an impaired therapeutic response. This culminates in an extremely poor clinical outcome. Our study reveals a novel regulatory mechanism underlying drug resistance and suggests that TRIB2 functions as a regulatory component of the PI3K network, activating AKT in cancer cells.
authors.affiliation: Department of Biomedical Sciences and Medicine (DCBM), University of Algarve, Campus de Gambelas, Faro 8005-139, Portugal.|Centre for Biomedical Research (CBMR), University of Algarve, Campus de Gambelas, Faro 8005-139, Portugal.|Brain Tumour Research Centre, Institute of Biomedical and Biomolecular Sciences, University of Portsmouth, PO1 2DT Portsmouth, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Hill
authors.affiliation: Centre for Biomedical Research (CBMR), University of Algarve, Campus de Gambelas, Faro 8005-139, Portugal.
authors.forename: Patricia A
authors.identifier: 0000-0002-4856-3908
authors.initials: PA
authors.lastname: Madureira
authors.affiliation: Centre for Biomedical Research (CBMR), University of Algarve, Campus de Gambelas, Faro 8005-139, Portugal.
authors.forename: Bibiana
authors.initials: B
authors.lastname: Ferreira
authors.affiliation: Centre for Biomedical Research (CBMR), University of Algarve, Campus de Gambelas, Faro 8005-139, Portugal.
authors.forename: Inês
authors.initials: I
authors.lastname: Baptista
authors.affiliation: Centre for Biomedical Research (CBMR), University of Algarve, Campus de Gambelas, Faro 8005-139, Portugal.
authors.forename: Susana
authors.initials: S
authors.lastname: Machado
authors.affiliation: Centre for Biomedical Research (CBMR), University of Algarve, Campus de Gambelas, Faro 8005-139, Portugal.
authors.forename: Laura
authors.initials: L
authors.lastname: Colaço
authors.affiliation: Centre for Biomedical Research (CBMR), University of Algarve, Campus de Gambelas, Faro 8005-139, Portugal.
authors.forename: Marta
authors.initials: M
authors.lastname: Dos Santos
authors.affiliation: Bayer AG, Drug Discovery Oncology Research, Berlin D-13342, Germany.
authors.forename: Ningshu
authors.initials: N
authors.lastname: Liu
authors.affiliation: Genomics Unit, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Dopazo
authors.affiliation: Department of Dermatology, University Hospital Essen, Essen 45147, Germany.
authors.forename: Selma
authors.initials: S
authors.lastname: Ugurel
authors.affiliation: Department of Cardiovascular Science, University of Sheffield, Sheffield S10 2RX, UK.
authors.forename: Angyal
authors.initials: A
authors.lastname: Adrienn
authors.affiliation: Department of Cardiovascular Science, University of Sheffield, Sheffield S10 2RX, UK.
authors.forename: Endre
authors.initials: E
authors.lastname: Kiss-Toth
authors.affiliation: Department of Molecular Biology and Genetics, Bilkent University, Ankara 06533, Turkey.
authors.forename: Murat
authors.initials: M
authors.lastname: Isbilen
authors.affiliation: Department of Molecular Biology and Genetics, Bilkent University, Ankara 06533, Turkey.
authors.forename: Ali O
authors.initials: AO
authors.lastname: Gure
authors.affiliation: Department of Biomedical Sciences and Medicine (DCBM), University of Algarve, Campus de Gambelas, Faro 8005-139, Portugal.|Centre for Biomedical Research (CBMR), University of Algarve, Campus de Gambelas, Faro 8005-139, Portugal.|Algarve Biomedical Center (ABC), University of Algarve, Campus de Gambelas, Faro 8005-139, Portugal.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Link
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D000071316:Forkhead Box Protein O3 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology; D034622:RNA Interference; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D000071316:Forkhead Box Protein O3; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D051736:Proto-Oncogene Proteins c-mdm2; D011804:Quinolines; C499517:FOXO3 protein, human; C497206:MDM2 protein, human; C489044:TRIB2 protein, human; C531198:dactolisib