TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT

Date
2017
Authors
Hill, R.
Madureira, P. A.
Ferreira, B.
Baptista, I.
Machado, S.
Colaço, L.
Dos Santos, M.
Liu, N.
Dopazo, A.
Ugurel, S.
Advisor
Instructor
Source Title
Nature Communications
Print ISSN
2041-1723
Electronic ISSN
1077-3118
Publisher
Nature Publishing Group
Volume
8
Issue
Pages
1 - 9
Language
English
Type
Article
Journal Title
Journal ISSN
Volume Title
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.

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Keywords
Benzyloxycarbonylleucylleucylleucinal, BIM protein, Caspase 3, CCAAT enhancer binding protein alpha, Copanlisib, Dacarbazine, Dactinomycin, Dactolisib, FasLG protein, Fluorouracil, Gemcitabine, Mammalian target of rapamycin complex 1, Mammalian target of rapamycin complex 2, Paclitaxel, Phosphatidylinositol 3 kinase, Protein, Protein kinase B, Protein MDM2, Protein p53, Protein serine threonine kinase, Rapamycin, Transcription factor FKHRL1, Transcription factor FOXO, Tribbles homologue 2 protein, Tumor necrosis factor related apoptosis inducing ligand, Ubiquitin protein ligase COP1, Ubiquitin protein ligase E3, Unclassified drug, Cancer, Cells and cell components, Chemotherapy, Drug resistance, Eenzyme, Enzyme activity, Gene expression, Metabolism, Protein, Animal experiment, Animal model, Article, Cancer combination chemotherapy, Cancer prognosis, Cancer resistance, Cancer survival, Cancer therapy, Cell metabolism, Cell proliferation, Cell survival, Clinical outcome, Colon cancer, Controlled study, Enzyme activation, Female, Human, Human cell, Human tissue, Malignant neoplasm, Melanoma, Metastatic melanoma, Mouse, Nonhuman, Pancreas cancer, Protein expression, Protein function, Protein phosphorylation, Protein targeting, Regulatory mechanism, Treatment response
Citation
Published Version (Please cite this version)