Browsing by Author "Hill, Richard"
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- Retraction note: TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKTPublication . Hill, Richard; Madureira, Patricia; Ferreira, Bibiana; Baptista, Ines; Machado, Susana; Colaҫo, Laura; dos Santos, Marta; Liu, Ningshu; Dopazo, Ana; Ugurel, Selma; Adrienn, Angyal; Kiss-Toth, Endre; Isbilen, Murat; Gure, Ali O.; Link, WolfgangThe authors have retracted this article as it has come to their attention that several images were inappropriately processed and duplicated in multiple figures. In particular, the data were duplicated, and in some cases inverted, across several panels in Figures 2c, 2b, 3d and Supplementary Figure 5. Erroneous data were also included in Figure 2e, Supplementary Figure 1 and Supplementary Figure 8. We apologize to the scientific community for any confusion this article may have caused. Richard Hill, Patricia Madureira, Bibiana I. Ferreira, Susana Machado, Ana Dopazo, Selma Ugurel, Endre Kiss-Toth, Murat isbilen and Wolfgang Link agree with this retraction. Inês Baptista, Laura Colaço, Marta dos Santos, Ningshu Liu, Angyal Adrienn and Ali O. Gure have not responded to correspondence from the Publisher about this retraction.
- Targeting nucleocytoplasmic transport in cancer therapyPublication . Hill, Richard; Cautain, Bastien; de Pedro, Nuria; Link, WolfgangThe intracellular location and regulation of proteins within each cell is critically important and is typically deregulated in disease especially cancer. The clinical hypothesis for inhibiting the nucleo-cytoplasmic transport is based on the dependence of certain key proteins within malignant cells. This includes a host of well-characterized tumor suppressor and oncoproteins that require specific localization for their function. This aberrant localization of tumour suppressors and oncoproteins results in their their respective inactivation or over-activation. This incorrect localization occurs actively via the nuclear pore complex that spans the nuclear envelope and is mediated by transport receptors. Accordingly, given the significant need for novel, specific disease treatments, the nuclear envelope and the nuclear transport machinery have emerged as a rational therapeutic target in oncology to restore physiological nucleus/cytoplasmic homeostasis. Recent evidence suggests that this approach might be of substantial therapeutic use. This review summarizes the mechanisms of nucleocytoplasmic transport, its role in cancer biology and the therapeutic potential of targeting this critical cellular process
- TRIB2 as a biomarker for diagnosis and progression of melanomaPublication . Hill, Richard; Kalathur, Ravi Kiran Reddy; Colaco, Laura; Brandao, Ricardo; Ugurel, Selma; Futschik, Matthias; Link, WolfgangMalignant melanoma is the most deadly form of skin cancer. There is a critical need to identify the patients that could be successfully treated by surgery alone and those that require adjuvant treatment. In this study, we demonstrate that the expression of tribbles2 (TRIB2) strongly correlates with both the presence and progression of melanocyte-derived malignancies. We examined the expression of TRIB2 in addition to 12 previously described melanoma biomarkers across three independent full genome microarray studies. TRIB2 expression was consistently and significantly increased in benign nevi and melanoma, and was highest in samples from patients with metastatic melanoma. The expression profiles for the 12 biomarkers were poorly conserved throughout these studies with only TYR, S100B and SPP1 showing consistently elevated expression in metastatic melanoma versus normal skin. Strikingly we confirmed these findings in 20 freshly obtained primary melanoma tissue samples from metastatic lesions where the expression of these biomarkers were evaluated revealing that TRIB2 expression correlated with disease stage and clinical prognosis. Our results suggest that TRIB2 is a meaningful biomarker reflecting diagnosis and progression of melanoma, as well as predicting clinical response to chemotherapy.
- TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKTPublication . Hill, Richard; Madureira, Patricia; Ferreira, Bibiana; Baptista, Inês; Machado, S.; Colaco, Laura; dos Santos, Marta; Liu, Ningshu; Dopazo, Ana; Ugurel, Selma; Adrienn, Angyal; Kiss-Toth, Endre; Isbilen, Murat; Gure, Ali O.; Link, WolfgangIntrinsic 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.