title: Plasminogen activator inhibitor-1 enhances radioresistance and aggressiveness of non-small cell lung cancer cells.
abstract: Acquired resistance of tumor cells during treatment limits the clinical efficacy of radiotherapy. Recent studies to investigate acquired resistance under treatment have focused on intercellular communication because it promotes survival and aggressiveness of tumor cells, causing therapy failure and tumor relapse. Accordingly, a better understanding of the functional communication between subpopulations of cells within a tumor is essential to development of effective cancer treatment strategies. Here, we found that conditioned media (CM) from radioresistant non-small cell lung cancer (NSCLC) cells increased survival of radiosensitive cells. Comparative proteomics analysis revealed plasminogen activator inhibitor-1 (PAI-1) as a key molecule in the secretome that acts as an extracellular signaling trigger to strengthen resistance to radiation. Our results revealed that expression and secretion of PAI-1 in radioresistant cells was increased by radiation-induced transcription factors, including p53, HIF-1α, and Smad3. When CM from radioresistant cells was applied to radiosensitive cells, extracellular PAI-1 activated the AKT and ERK1/2 signaling pathway and inhibited caspase-3 activity. Our study also proposed that PAI-1 activates the signaling pathway in radiosensitive cells via extracellular interaction with its binding partners, not clathrin-mediated endocytosis. Furthermore, secreted PAI-1 increased cell migration capacity and expression of EMT markers in vitro and in vivo. Taken together, our findings demonstrate that PAI-1 secreted from radioresistant NSCLC cells reduced radiosensitivity of nearby cells in a paracrine manner, indicating that functional inhibition of PAI-1 signaling has therapeutic potential because it prevents sensitive cells from acquiring radioresistance.
authors.affiliation: Department of Integrated Biological Science, Pusan National University, Busan, 46241, Republic of Korea.
authors.forename: JiHoon
authors.initials: J
authors.lastname: Kang
authors.affiliation: Department of Biological Sciences, Pusan National University, Busan 46241, Republic of Korea.|Nuclear Science Research Institute, Pusan National University, Busan 46241, Republic of Korea.
authors.forename: Wanyeon
authors.initials: W
authors.lastname: Kim
authors.affiliation: Department of Integrated Biological Science, Pusan National University, Busan, 46241, Republic of Korea.
authors.forename: TaeWoo
authors.initials: T
authors.lastname: Kwon
authors.affiliation: Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul 05006, Republic of Korea.
authors.forename: HyeSook
authors.initials: H
authors.lastname: Youn
authors.affiliation: Research Center, Dongnam Institute of Radiological and Medical Sciences, Busan 46033, Republic of Korea.
authors.forename: Joong Sun
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Department of Integrated Biological Science, Pusan National University, Busan, 46241, Republic of Korea.|Department of Biological Sciences, Pusan National University, Busan 46241, Republic of Korea.|Nuclear Science Research Institute, Pusan National University, Busan 46241, Republic of Korea.
authors.forename: BuHyun
authors.initials: B
authors.lastname: Youn
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D049109:Cell Proliferation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D011836:Radiation Tolerance; D015398:Signal Transduction / Q000528:radiation effects; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014965:X-Rays; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; C497790:SMAD3 protein, human; D051900:Smad3 Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: EMT; NSCLC; PAI-1; paracrine; radioresistance