TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT
Authors: Ali O Gure
Bibiana Ferreira
Marta Dos Santos
Richard Hill
Endre Kiss-Toth
Ningshu Liu
Susana Machado
Ana Dopazo
Wolfgang Link
Selma Ugurel
Angyal Adrienn
Inês Baptista
Laura Colaço
Patricia A Madureira
Murat Isbilen
Journal: Nature communications (2017)
Discipline: Multidisciplinary
Keywords: chemotherapy resistance; TRIB2; drug resistance; AKT; FOXO3a
Affiliations: Department of Biomedical Sciences and Medicine (DCBM), University of Algarve, Campus de Gambelas, Faro 8005-139, Portugal., Centre for Biomedical Research (CBMR), University of Algarve, Campus de Gambelas, Faro 8005-139, Portugal., Brain Tumour Research Centre, Institute of Biomedical and Biomolecular Sciences, University of Portsmouth, PO1 2DT Portsmouth, UK., Bayer AG, Drug Discovery Oncology Research, Berlin D-13342, Germany., Genomics Unit, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain., Department of Dermatology, University Hospital Essen, Essen 45147, Germany., Department of Cardiovascular Science, University of Sheffield, Sheffield S10 2RX, UK., Department of Molecular Biology and Genetics, Bilkent University, Ankara 06533, Turkey., Algarve Biomedical Center (ABC), University of Algarve, Campus de Gambelas, Faro 8005-139, Portugal.

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. 

Retracted: No

PubPeer comments:
 Figure 2:  (c) Temporal inhibition of PI3K-dependent signalling following exposure to PI3K inhibitors. Total protein lysate of 50u2013200 mg was loaded per lane and separated by 6u201312% SDSu2013PAGE . I started marking the pairs of surprisingly-similar protein bands but ran out of colors. In some of the pairs, the similarity is masked somewhat by horizontal flips, or compression, or change in intensity, or combinations thereof. ![file] , 
 Figure 2(b), I d like to introduce you to Figure 3(d)... ah, but I see you ve already met. ![file] Update: My bad for not noticing that the same band also appears in Fig 2(c), there identified as  Total FOXO3a rather than as  beta-actin or  Total AKT . But the authors and reviewers didn t notice either so I don t feel **too** bad. , 
 Juxtaposing another column from Fig 2(c) against Fig 3(h), because why not? ![file] Update: Let s bring Fig 3(d) into the mix. ![file] , 
 The uncropped (and evidently unenhanced, contrast corrected, uncompressed etc.) blots are in the SI and are well worth a close look. For example, #3 by Hoya: ![file] , 
 #1 The similarity of total AKT and total FOXO3a bands you highlight is perhaps more striking in all its SI full blot glory: ![file] , 
 The sheer scale and murkiness of Figure 4(e) are destroying my will to live, and I cannot face the prospect of wading into Supplementary Figures to inspect the original gels. I will content myself with a single comparison with the upper left section of Fig 2(c). ![file] , 
 #1 - #6 : This is truly heroic work, Hoya. Regarding #6, the Supplementary Material (seemingly starved for pixels) does indeed confirm your point: the same blot is claimed to represent two different things (total AKT for Fig 2c, or actin for Fig 4d). What a royal mess. *Edit Update: comment #5 shows that this same blot is ALSO claimed to be total FOXO3a. Hard to keep it all straight.* ![file] , 
 We thank Hoya Camphorifolia for their diligence and for the comments that they (and Sicarius) have raised. We would like to highlight that myself (and the corresponding author) spotted and highlighted these concerns on April 10th, 2017 where we submitted a full amendment, addressing in particular, the concerns raised in Figure 2c. and 3d. We emphasize that we noticed these and informed the journal many years prior to these comments being posted on the PubPeer site. We have again notified the journal on August 14th, 2019 providing again our original data, entire panels and full uncropped images. We highlight to the research and PubPeer community that our amendment does not alter any of our conclusions in this highly cited manuscript and indicate that these findings have been replicated in a number of independent laboratories. All authors resolutely stand behind all conclusions within this important publication. We apologise for these errors and all involved will ensure that similar mistakes are never made again. Sincerely, Prof. Wolfgang Link (Corresp.) Dr. Richard Hill (1st author). , 
 #8 Thanks for your response and congratulations on your citations. Where is the full amendment out of interest? Unless I have missed it, Nature Communications don t have a Corrigendum for this article. Which is surprising - and disappointing - if you contacted them just over 2 years ago. Those errors compromise 2 out of 4 of the manuscript s figures and those flipped and re-used blots were for TRIB2 and AKT; two of the main proteins in your paper. I thought Nature online journals were fairly good at putting corrections online and updating the manuscript. , 
 Prof Link and Dr Hill? Why did Nature Communications not publish the full amendment you submitted over 2 years ago to correct the manuscript? , 
 Judging from the lack of reply to my query and the fact there is still no correction to this paper I think we can assume no correction was ever submitted to Nature Communications. This paper remains published and [severely] compromised. ,