TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT
Madureira, P. A.
Dos Santos, M.
Gure, A. O.
Nature Publishing Group
1 - 9
Item Usage Stats
MetadataShow full item record
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.
CCAAT enhancer binding protein alpha
Mammalian target of rapamycin complex 1
Mammalian target of rapamycin complex 2
Phosphatidylinositol 3 kinase
Protein kinase B
Protein serine threonine kinase
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
Cells and cell components
Cancer combination chemotherapy
Published Version (Please cite this version)http://dx.doi.org/10.1038/ncomms14687
Showing items related by title, author, creator and subject.
The miR-644a/CTBP1/p53 axis suppresses drug resistance by simultaneous inhibition of cell survival and epithelialmesenchymal transition in breast cancer Raza, U.; Saatci, O.; Uhlmann, S.; Ansari, S. A.; Eyüpoglu, E.; Yurdusev, E.; Mutlu, M.; Ersan, P. G.; Altundağ, M. K.; Zhang, J. D.; Dogan, H. T.; Güler, G.; Şahin, Ö. (Impact Journals LLC, 2016)Tumor cells develop drug resistance which leads to recurrence and distant metastasis. MicroRNAs are key regulators of tumor pathogenesis; however, little is known whether they can sensitize cells and block metastasis ...
The prosurvival IKK-related kinase IKKϵ integrates LPS and IL17A signaling cascades to promote Wnt-dependent tumor development in the intestine Göktuna, S. I.; Shostak, K.; Chau, T.-L.; Heukamp, L.C.; Hennuy, B.; Duong, H.-Q.; Ladang, A.; Close, P.; Klevernic, I.; Olivier, F.; Florin, A.; Ehx, G.; Baron, F.; Vandereyken, M.; Rahmouni, S.; Vereecke, L.; Loo, G. V.; Büttner, R.; Greten, F. R.; Chariot, A. (American Association for Cancer Research, 2016-05)Constitutive Wnt signaling promotes intestinal cell proliferation, but signals from the tumor microenvironment are also required to support cancer development. The role that signaling proteins play to establish a tumor ...
Quantification of SLIT-ROBO transcripts in hepatocellular carcinoma reveals two groups of genes with coordinate expression Avci, M. E.; Konu, O.; Yagci, T. (BioMed Central, 2008)Background: SLIT-ROBO families of proteins mediate axon pathfinding and their expression is not solely confined to nervous system. Aberrant expression of SLIT-ROBO genes was repeatedly shown in a wide variety of cancers, ...