RETRACTED ARTICLE: TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT

Richard Hill, Patricia A. Madureira, Bibiana Ferreira, Inês Baptista, Susana Machado, Laura Colaço, Marta dos Santos, Ningshu Liu, Ana Dopazo, Selma Ugurel, Angyal Adrienn, Endre Kiss-Toth, Murat Isbilen, Ali O. Gure and Wolfgang Link ()
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Richard Hill: University of Algarve
Patricia A. Madureira: Centre for Biomedical Research (CBMR), University of Algarve
Bibiana Ferreira: Centre for Biomedical Research (CBMR), University of Algarve
Inês Baptista: Centre for Biomedical Research (CBMR), University of Algarve
Susana Machado: Centre for Biomedical Research (CBMR), University of Algarve
Laura Colaço: Centre for Biomedical Research (CBMR), University of Algarve
Marta dos Santos: Centre for Biomedical Research (CBMR), University of Algarve
Ningshu Liu: Bayer AG, Drug Discovery Oncology Research
Ana Dopazo: Genomics Unit, Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Selma Ugurel: University Hospital Essen
Angyal Adrienn: University of Sheffield
Endre Kiss-Toth: University of Sheffield
Murat Isbilen: Bilkent University
Ali O. Gure: Bilkent University
Wolfgang Link: University of Algarve

Nature Communications, 2017, vol. 8, issue 1, 1-9

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14687

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