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
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Wei-Ling Chang1,2, Lih-Ching Hsu2, Wohn-Jenn Leu2, Ching-Shih Chen1, Jih-Hwa Guh2
1The Division of Medicinal Chemistry, College of Pharmacy, Ohio State University, Columbus, OH 43210, USA
2School of Pharmacy, National Taiwan University, Taipei 100, Taiwan
Ching-Shih Chen, e-mail: firstname.lastname@example.org
Jih-Hwa Guh, e-mail: email@example.com
Keywords: Nitroxoline, AMPK/mTOR signaling, Chk2, G1 arrest, Cyclin D1-Rb-Cdc25A axis
Received: July 10, 2015 Accepted: September 21, 2015 Published: October 03, 2015
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 AMPKα 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.
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