TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT
Author
Hill, R.
Madureira, P. A.
Ferreira, B.
Baptista, I.
Machado, S.
Colaço, L.
Dos Santos, M.
Liu, N.
Dopazo, A.
Ugurel, S.
Adrienn, A.
Kiss-Toth, E.
Isbilen, M.
Gure, A. O.
Link, W.
Date
2017Source Title
Nature Communications
Print ISSN
2041-1723
Electronic ISSN
1077-3118
Publisher
Nature Publishing Group
Volume
8
Pages
1 - 9
Language
English
Type
ArticleItem Usage Stats
175
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104
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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.
Keywords
BenzyloxycarbonylleucylleucylleucinalBIM 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
Permalink
http://hdl.handle.net/11693/37271Published Version (Please cite this version)
http://dx.doi.org/10.1038/ncomms14687Collections
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