title: PIM1-activated PRAS40 regulates radioresistance in non-small cell lung cancer cells through interplay with FOXO3a, 14-3-3 and protein phosphatases.
abstract: Resistance of cancer cells to ionizing radiation plays an important role in the clinical setting of lung cancer treatment. To date, however, the exact molecular mechanism of radiosensitivity has not been well explained. In this study, we compared radioresistance in two types of non-small cell lung cancer (NSCLC) cells, NCI-H460 and A549, and investigated the signaling pathways that confer radioresistance. In radioresistant cells, exposure to radiation led to overexpression of PIM1 and reduction of protein phosphatases (PP2A and PP5), which induced translocation of PIM1 into the nucleus. Increased nuclear PIM1 phosphorylated PRAS40. Consequently, pPRAS40 made a trimeric complex with 14-3-3 and AKT-activated pFOXO3a, which then moved rapidly to the cytoplasm. Cytoplasmic retention of FOXO3a was associated with downregulation of proapoptotic genes and possibly radioresistance. On the other hand, no suppressive effect of radiation on protein phosphatases was detected and, concomitantly, protein phosphatases downregulated PIM1 in radiosensitive cells. In this setting, PIM1-activated pPRAS40, AKT-activated pFOXO3a, and their complex formation with 14-3-3 could be key regulators of the radiation-induced radioresistance in NSCLC cells.
authors.affiliation: College of Natural Sciences, Department of Biological Sciences, Pusan National University, Busan, South Korea.
authors.forename: Wanyeon
authors.initials: W
authors.lastname: Kim
authors.forename: HyeSook
authors.initials: H
authors.lastname: Youn
authors.forename: Ki Moon
authors.initials: KM
authors.lastname: Seong
authors.forename: Hee Jung
authors.initials: HJ
authors.lastname: Yang
authors.forename: Young Ju
authors.initials: YJ
authors.lastname: Yun
authors.forename: TaeWoo
authors.initials: T
authors.lastname: Kwon
authors.forename: Young Ha
authors.initials: YH
authors.lastname: Kim
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Young-Woo
authors.initials: YW
authors.lastname: Jin
authors.forename: BuHyun
authors.initials: B
authors.lastname: Youn
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D003593:Cytoplasm / Q000378:metabolism / Q000528:radiation effects; D004789:Enzyme Activation / Q000528:radiation effects; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation / Q000528:radiation effects; D055503:Protein Multimerization / Q000528:radiation effects; D020836:Protein Structure, Quaternary; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism*; D011836:Radiation Tolerance; D015398:Signal Transduction / Q000528:radiation effects
chemical_list: D048948:14-3-3 Proteins; C484523:AKT1S1 protein, human; D048868:Adaptor Proteins, Signal Transducing; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D009687:Nuclear Proteins; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1; D010749:Phosphoprotein Phosphatases; C089641:protein phosphatase 5