title: mTOR regulates proteasomal degradation and Dp1/E2F1- mediated transcription of KPNA2 in lung cancer cells.
abstract: Karyopherin subunit alpha-2 (KPNA2) is overexpressed in various human cancers and is associated with cancer invasiveness and poor prognosis in patient. Nevertheless, the regulation of KPNA2 expression in cancers remains unclear. We herein applied epidermal growth factor (EGF) and five EGF receptor (EGFR)-related kinase inhibitors to investigate the role of EGFR signaling in KPNA2 expression in non-small cell lung cancer (NSCLC) cells. We found that EGFR signaling, particularly the mammalian target of rapamycin (mTOR) activity was positively correlated with KPNA2 protein levels in NSCLC cells. The mTOR inhibitors and mTOR knockdown reduced the protein and mRNA levels of KPNA2 in NSCLC and breast cancer cells. Specifically, rapamycin treatment induced proteasome-mediated KPNA2 protein decay and attenuated the transcriptional activation of KPNA2 by decreasing Dp1/E2F1 level in vivo. Immunoprecipitation assay further revealed that KPNA2 physically associated with the phospho-mTOR/mTOR and this association was abolished by rapamycin treatment. Collectively, our results show for the first time that KPNA2 is transcriptionally and post-translationally regulated by the mTOR pathway and provide new insights into targeted therapy for NSCLC.
authors.affiliation: Molecular Medicine Research Center, Chang Gung University, Tao-Yuan, Taiwan.
authors.forename: Chun-I
authors.initials: CI
authors.lastname: Wang
authors.affiliation: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
authors.forename: Yan-Yu
authors.initials: YY
authors.lastname: Chen
authors.affiliation: Department of Thoracic Medicine, Chang Gung Memorial Hospital, Linkou, Tao-Yuan, Taiwan.
authors.forename: Chih-Liang
authors.initials: CL
authors.lastname: Wang
authors.affiliation: Molecular Medicine Research Center, Chang Gung University, Tao-Yuan, Taiwan.|Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.|Department of Cell and Molecular Biology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
authors.forename: Jau-Song
authors.initials: JS
authors.lastname: Yu
authors.affiliation: Molecular Medicine Research Center, Chang Gung University, Tao-Yuan, Taiwan.|Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
authors.forename: Yu-Sun
authors.initials: YS
authors.lastname: Chang
authors.affiliation: Molecular Medicine Research Center, Chang Gung University, Tao-Yuan, Taiwan.|Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.|Department of Cell and Molecular Biology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.|Department of Thoracic Medicine, Chang Gung Memorial Hospital, Linkou, Tao-Yuan, Taiwan.
authors.forename: Chia-Jung
authors.initials: CJ
authors.lastname: Yu
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D050687:E2F1 Transcription Factor / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D050680:Transcription Factor DP1 / Q000378:metabolism; D028901:alpha Karyopherins / Q000096:biosynthesis*
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C490630:KPNA2 protein, human; D050680:Transcription Factor DP1; D028901:alpha Karyopherins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex
keywords: E2F1; EGFR; KPNA2; lung cancer; mTOR