https://scholars.lib.ntu.edu.tw/handle/123456789/564779
標題: | Repurposing of nitroxoline as a potential anticancer agent against human prostate cancer - A crucial role on AMPK/mTOR signaling pathway and the interplay with Chk2 activation | 作者: | Chang W.-L. LIH-CHING HSU Leu W.-J. Chen C.-S. JIH-HWA GUH |
公開日期: | 2015 | 卷: | 6 | 期: | 37 | 起(迄)頁: | 39806-39820 | 來源出版物: | Oncotarget | 摘要: | Nitroxoline is an antibiotic by chelating Zn2+ and Fe2+ from biofilm matrix. In this study, nitroxoline induced G1 arrest of cell cycle and subsequent apoptosis in prostate cancer cells through ion chelating-independent pathway. It decreased protein levels of cyclin D1, Cdc25A and phosphorylated Rb, but activated AMP-activated protein kinase (AMPK), a cellular energy sensor and signal transducer, leading to inhibition of downstream mTOR-p70S6K signaling. Knockdown of AMPKa significantly rescued nitroxoline-induced inhibition of cyclin D1-Rb-Cdc25A axis indicating AMPK-dependent mechanism. However, cytoprotective autophagy was simultaneously evoked by nitroxoline. Comet assay and Western blot analysis demonstrated DNA damaging effect and activation of Chk2 other than Chk1 to nitroxoline action. Instead of serving as a DNA repair transducer, nitroxoline-mediated Chk2 activation was identified to function as a pro-apoptotic inducer. In conclusion, the data suggest that nitroxoline induces anticancer activity through AMPK-dependent inhibition of mTOR-p70S6K signaling pathway and cyclin D1-Rb-Cdc25A axis, leading to G1 arrest of cell cycle and apoptosis. AMPK-dependent activation of Chk2, at least partly, contributes to apoptosis. The data suggest the potential role of nitroxoline for therapeutic development against prostate cancers. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84950159747&doi=10.18632%2foncotarget.5655&partnerID=40&md5=842ffff19fc75af4f8c17a95a98e678e https://scholars.lib.ntu.edu.tw/handle/123456789/564779 |
ISSN: | 19492553 | DOI: | 10.18632/oncotarget.5655 | SDG/關鍵字: | Cdc25A protein; cell cycle protein; cell DNA; checkpoint kinase 1; checkpoint kinase 2; cyclin D1; hydroxymethylglutaryl coenzyme A reductase kinase; mammalian target of rapamycin; nitroxoline; retinoblastoma protein; S6 kinase; unclassified drug; antineoplastic agent; CDC25A protein, human; checkpoint kinase 2; CHEK2 protein, human; cyclin D1; hydroxymethylglutaryl coenzyme A reductase kinase; nitroquinoline derivative; nitroxoline; protein tyrosine phosphatase; retinoblastoma protein; target of rapamycin kinase; antineoplastic activity; apoptosis; Article; cancer cell; cell energy; cell protection; controlled study; DNA damage; enzyme activation; enzyme inhibition; enzyme regulation; G1 phase cell cycle checkpoint; human; human cell; prostate cancer; protein binding; protein phosphorylation; protein protein interaction; signal transduction; apoptosis; cell proliferation; drug effects; drug repositioning; fluorescence microscopy; G1 phase cell cycle checkpoint; genetics; male; metabolism; pathology; prostate tumor; RNA interference; tumor cell line; Western blotting; AMP-Activated Protein Kinases; Antineoplastic Agents; Apoptosis; Blotting, Western; cdc25 Phosphatases; Cell Line, Tumor; Cell Proliferation; Checkpoint Kinase 2; Cyclin D1; DNA Damage; Drug Repositioning; Enzyme Activation; G1 Phase Cell Cycle Checkpoints; Humans; Male; Microscopy, Fluorescence; Nitroquinolines; Prostatic Neoplasms; Retinoblastoma Protein; RNA Interference; Signal Transduction; TOR Serine-Threonine Kinases |
顯示於: | 藥學系 |
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