Research developed at the University of Algarve can help improve the effectiveness of cancer treatments

Authors and affiliations:
Richard Hill - DCBM/UAlg/ Brain Tumour Center (Portsmouth);

Patrícia A. Madureira - CBMR;

Bibiana Ferreira - CBMR;

Inês Baptista - CBMR;

Susana Machado - CBMR;

Laura Colaço- CBMR;

Marta dos Santos - CBMR;

Ningshu Liu - Bayer AG;

Ana Dopazo - 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 - DCBM/ UAlg/ CBMR/ ABC (Algarve Biomedical Center)

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.

Journal: Nature Communications

Link: http://www.nature.com/articles/ncomms14687