Blockade of the LRP16-PKR-NF-κB signaling axis sensitizes colorectal carcinoma cells to DNA-damaging cytotoxic therapy.

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http://hdl.handle.net/10138/225287

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Li , X , Wu , Z , An , X , Mei , Q , Bai , M , Hanski , L , Li , X , Ahola , T & Han , W 2017 , ' Blockade of the LRP16-PKR-NF-κB signaling axis sensitizes colorectal carcinoma cells to DNA-damaging cytotoxic therapy. ' , eLife , vol. 6 , e27301 . https://doi.org/10.7554/eLife.27301

Title: Blockade of the LRP16-PKR-NF-κB signaling axis sensitizes colorectal carcinoma cells to DNA-damaging cytotoxic therapy.
Author: Li, Xiaolei; Wu, Zhiqiang; An, Xiaojing; Mei, Qian; Bai, Miaomiao; Hanski, Leena; Li, Xiang; Ahola, Tero; Han, Weidong
Contributor: University of Helsinki, Faculty of Pharmacy
University of Helsinki, Department of Food and Nutrition
Date: 2017
Language: eng
Number of pages: 34
Belongs to series: eLife
ISSN: 2050-084X
URI: http://hdl.handle.net/10138/225287
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 IKK beta, prolonging the polymers of ADP-ribose (PAR)-dependent nuclear factor kappa B (NF-kappa B) 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 IKK beta, 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.
Subject: 3111 Biomedicine
317 Pharmacy
NF-KAPPA-B
PROTEIN-KINASE PKR
ESTROGEN-RECEPTOR-ALPHA
COLON-CANCER
ADJUVANT CHEMOTHERAPY
GENOTOXIC STRESS
DRUG-RESISTANCE
BREAST-CANCER
ACTIVATION
RNA
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