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Inflammation-induced radioresistance is mediated by ROS-dependent inactivation of protein phosphatase 1 in non-small cell lung cancer cells

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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.

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Acknowledgments

This work was supported by Radiation Technology R&D program through the NRF funded by the MSIP (2013M2A2A7042502), a grant from the National R&D Program for Cancer Control, MOHW (1320100), Basic Science Research Program through the NRF funded by the MSIP (2014R1A1A1A05002112), and Basic Science Research Program through the NRF funded by the MOE (2013R1A1A2059832 to W Kim and 2014R1A1A2004061 to H Youn). In addition, this research was financially supported by the Ministry of Education (MOE) and National Research Foundation of Korea (NRF) through the Human Resource Training Project for Regional Innovation (2012H1B8A2026225).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Nuclear Science Research Institute, Pusan National University, Busan, 609-735, South Korea

    Wanyeon Kim, HyeSook Youn & BuHyun Youn

  2. Department of Biological Sciences, Pusan National University, Busandaehak-ro 63beon-gil, Guemjeong-gu, Busan, 609-735, South Korea

    Wanyeon Kim, HyeSook Youn & BuHyun Youn

  3. Department of Chemistry, Washington State University, Pullman, WA, 99164, USA

    ChulHee Kang

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  1. Wanyeon Kim
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Correspondence to BuHyun Youn.

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Kim, W., Youn, H., Kang, C. et al. Inflammation-induced radioresistance is mediated by ROS-dependent inactivation of protein phosphatase 1 in non-small cell lung cancer cells. Apoptosis 20, 1242–1252 (2015). https://doi.org/10.1007/s10495-015-1141-1

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