Abstract
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.
Highlights
Development of new chemical entities is costly and time-consuming
Activated Chk2 protein kinase serves as a signal transducer, phosphorylating a wide variety of substrates including cell division cycle 25 (Cdc25) family members, promyelocytic leukemia protein (PML), E2F-1, BRCA1 (BReast CAncer gene 1) and p53, which have been highly associated with regulating DNA damage response and repair, cell cycle arrest as well as apoptosis [3,4,5]
Overexpression of cyclin D1 has been detected in numerous types of cancers, including cancers of the breast, lung and prostate [34,35,36] and has been considered as an oncogenic mechanism in hormone-refractory metastatic prostate cancer to the bone [36]
Summary
Development of new chemical entities is costly and time-consuming. Drug repurposing ( known as drug repositioning), which refers to the discovery of new indications from existing drugs, has been a popular approach in recent years. Chk is a tumor susceptibility gene encoding for a serine/threonine protein kinase responsive to cellular DNA damage [3, 4]. Activated Chk protein kinase serves as a signal transducer, phosphorylating a wide variety of substrates including cell division cycle 25 (Cdc25) family members, promyelocytic leukemia protein (PML), E2F-1, BRCA1 (BReast CAncer gene 1) and p53, which have been highly associated with regulating DNA damage response and repair, cell cycle arrest as well as apoptosis [3,4,5]. During DNA damage response, Chk phosphorylates downstream substrates (e.g., BRCA1), leading to initiation of homologous recombination DNA repair signaling which may crossly interact nonhomologous end joining repair pathway [6, 7]. Based on the critical www.impactjournals.com/oncotarget role during DNA damage response and cell apoptosis, Chk has been suggested as a potential target for anticancer therapy
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