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

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.

• Authors: Xiaolei Li, Zhiqiang Wu, Xiaojing An, Qian Mei, Miaomiao Bai, Leena Hanski, Xiang Li, Tero Ahola, Weidong Han
• Journal: eLife (Elife) Vol. 6 (08 18 2017) ISSN: 2050-084X [Electronic] England
• PMID: 28820388 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Isothiocyanates
• N,N''-1,4-butanediylbis(N'-(3-isothiocyanatophenyl))thiourea
• NF-kappa B
• Neoplasm Proteins
• Etoposide
• DNA
• EIF2AK2 protein, human
• eIF-2 Kinase
• I-kappa B Kinase
• Carboxylic Ester Hydrolases
• MACROD1 protein, human
• Thiourea

Topics

• Animals
• Antineoplastic Agents (administration & dosage)
• Carboxylic Ester Hydrolases
• Cell Line, Tumor
• Colorectal Neoplasms (drug therapy)
• DNA (metabolism)
• Disease Models, Animal
• Drug Synergism
• Enzyme Inhibitors (administration & dosage)
• Etoposide (administration & dosage)
• Heterografts
• Humans
• I-kappa B Kinase (metabolism)
• Isothiocyanates (metabolism)
• Mice, Inbred BALB C
• Mice, Nude
• NF-kappa B (antagonists & inhibitors)
• Neoplasm Proteins (antagonists & inhibitors)
• Neoplasm Transplantation
• Protein Binding
• Signal Transduction
• Thiourea (analogs & derivatives, metabolism)
• Treatment Outcome
• eIF-2 Kinase (antagonists & inhibitors)