title: Inflammation-induced radioresistance is mediated by ROS-dependent inactivation of protein phosphatase 1 in non-small cell lung cancer cells.
abstract: Inflammation plays a pivotal role in modulating the radiation responsiveness of tumors. We determined that an inflammation response prior to irradiation contributes to radiotherapy resistance in non-small cell lung cancer (NSCLC) cells. In the clonogenic survival assay, activation of the inflammation response by lipopolysaccharide (LPS) decreased the degree of radiosensitivity in NCI-H460 cells (relatively radiosensitive cells), but had no effect in A549 cells (relatively radioresistant cells). LPS-induced radioresistance of NCI-H460 cells was also confirmed with a xenograft mouse model. The radioresistant effect observed in NCI-H460 cells was correlated with inhibition of apoptotic cell death due to reduced Caspase 3/7 activity. Moreover, we found that the levels of reactive oxygen species (ROS) were synergistically elevated in NCI-H460 cells by treatment with LPS and radiation. Increased ROS generation negatively affected the activity of protein phosphatase 1 (PP1). Decreased PP1 activity did not lead to Bad dephosphorylation, consequently resulting in the inhibition of irradiation-induced mitochondrial membrane potential loss and apoptosis. We confirmed that pre-treatment with a PP1 activator and LPS sensitized NCI-H460 cells to radiation. Taken together, our findings provided evidence that PP1 activity is critical for radiosensitization in NSCLC cells and PP1 activators can serve as promising radiosensitizers to improve therapeutic efficacy.
authors.affiliation: Nuclear Science Research Institute, Pusan National University, Busan, 609-735, South Korea.
authors.forename: Wanyeon
authors.initials: W
authors.lastname: Kim
authors.forename: HyeSook
authors.initials: H
authors.lastname: Youn
authors.forename: ChulHee
authors.initials: C
authors.lastname: Kang
authors.forename: BuHyun
authors.initials: B
authors.lastname: Youn
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D020536:Enzyme Activators / Q000494:pharmacology; D005720:Gamma Rays / Q000627:therapeutic use; D064593:Heterografts; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D011836:Radiation Tolerance / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D020536:Enzyme Activators; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D054645:Protein Phosphatase 1; D020169:Caspases