Blockade of the LRP16-PKR-NF-κB signaling axis sensitizes colorectal carcinoma cells to DNA-damaging cytotoxic therapy
Authors: Tero Ahola
Miaomiao Bai
Qian Mei
Xiaolei Li
Xiang Li
Zhiqiang Wu
Leena Hanski
Xiaojing An
Weidong Han
Journal: eLife (2017)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: DNA damage response; LRP16; NF-κB; acquired resistance; cancer biology
Affiliations: Department of Molecular Biology, Immunological and Bio-therapeutic, Institute of Basic Medicine, Chinese PLA General Hospital, Beijing, China., Department of Pathology, Chinese PLA General Hospital, Beijing, China., Department of Pathology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China., Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland., Department of Food and Environmental Sciences, University of Helsinki, Helsinki, Finland.

Abstract:  Acquired therapeutic resistance by tumors is a substantial impediment to reducing the morbidity and mortality that are attributable to human malignancies. The mechanisms responsible for the dramatic shift between chemosensitivity and chemoresistance in colorectal carcinoma have not been defined. Here, we report that LRP16 selectively interacts and activates double-stranded RNA-dependent kinase (PKR), and also acts as scaffolds to assist the formation of a ternary complex of PKR and IKKβ, prolonging the polymers of ADP-ribose (PAR)-dependent nuclear factor kappa B (NF-κB) transactivation caused by DNA-damaging agents and confers acquired chemoresistance. We also identified a small molecule, MRS2578, which strikingly abrogated the binding of LRP16 to PKR and IKKβ, converting LRP16 into a death molecule and forestalling colon tumorigenesis. Inclusion of MRS2578 with etoposide, versus each drug alone, exhibited synergistic antitumor cytotoxicity in xenografts. Our combinatorial approach introduces a strategy to enhance the efficacy of genotoxicity therapies for the treatment of tumors. 

Retracted: No

PubPeer comments:
 Dear authors, I noticed that a figure was duplicated and thought this likely a mistake (pink). However, then I realised that in the same image an area of cells appeared twice (yellow). From Fig. 6C ![file] When looking a bit more closely, in Supplementary Figure 2 A also a duplication is present ![file] I was also left wondering about the Western Blots: is there any explanation why the p65 shows an elevated band in the second lane, but the phospho-specific antibody, recognising the same protein albeit modified, sees a straight line? ![file] In general, I think many blots are overexposed and therefore hard to interpret. It would be great if the authors could share shorter exposures and also more details on cutting reprobing of blots. In this selection of Fig 3A for example, p65 is definitely overexposed. Also, IKKbeta  smiles down , the phospho-IKK is straight and p65  smiles up . Are these really from 1 blot? Would be great if the authors can clarify. ![file] , 
 Hi Karla L. H. Feijs, Thank you for raising this concern, which we have looked into very carefully. We regret that we accidentally used one picture twice when we processed and assembled the figures in the published version. Specifically, due to an oversight at the time of the manuscript publication, in the published version of Figure 6G, identical image file (Figure 6G, upper group) was used twice by accident at the time. Also, in the published version of Figure 2-figure supplement 2B, identical image file (Oxaliplatin group, middle panel) was used twice by accident at the time. As to this, we have contacted with and provided a formal erratum to the editorial office of eLife. In addition, identical batch of samples with the same quality, the same sequence and the same conditions to detect p65 and IKK and their phosphorylated forms were run on different gels. We sincerely apologize for this unintentional error made before manuscript submission but we failed to catch at the submission and subsequent proofreading. Great thanks you again for your careful reading of our paper and findings of our errors of panel duplication within one Figure. Sincerely, Weidong Han ,