Abstract
We recently identified nitroxoline as a repurposed drug candidate in pancreatic cancer (PC) showing a dose-dependent antiproliferative activity in different PC cell lines. This antibiotic is effective in several in vitro and animal cancer models. To date, the mechanisms of nitroxoline anticancer action are largely unknown. Using shotgun proteomics we identified 363 proteins affected by nitroxoline treatment in AsPC-1 pancreatic cancer cells, including 81 consistently deregulated at both 24- and 48-hour treatment. These proteins previously unknown to be affected by nitroxoline were mostly downregulated and interconnected in a single highly-enriched network of protein-protein interactions. Integrative proteomic and functional analyses revealed nitroxoline-induced downregulation of Na/K-ATPase pump and β-catenin, which associated with drastic impairment in cell growth, migration, invasion, increased ROS production and induction of DNA damage response. Remarkably, nitroxoline induced a previously unknown deregulation of molecules with a critical role in cell bioenergetics, which resulted in mitochondrial depolarization. Our study also suggests that deregulation of cytosolic iron homeostasis and of co-translational targeting to membrane contribute to nitroxoline anticancer action. This study broadens our understanding of the mechanisms of nitroxoline action, showing that the drug modulates multiple proteins crucial in cancer biology and previously unknown to be affected by nitroxoline.
Highlights
We recently identified nitroxoline as a repurposed drug candidate in pancreatic cancer (PC) showing a dose-dependent antiproliferative activity in different PC cell lines
To analyze mechanisms by which this antibacterial exerts its anticancer activity, several studies screened for specific candidate targets and molecular pathways known to play an important role in cancer biology[7,8,9,10,11,12,13,14,15,16,17,18,19]
The differentially expressed proteins were calculated for each biological replicate using 0.5% peptide-spectrum matches (PSM) FDR and the resulting ID lists were filtered considering only peptides identified in at least 3 out of 6 technical replicates, significance ≥20 (−10lgP), quality factor ≥0.5, Average Area ≥ 104, and by considering only proteins identified with significance ≥20 and fold change ≥2
Summary
We recently identified nitroxoline as a repurposed drug candidate in pancreatic cancer (PC) showing a dose-dependent antiproliferative activity in different PC cell lines. To analyze mechanisms by which this antibacterial exerts its anticancer activity, several studies screened for specific candidate targets and molecular pathways known to play an important role in cancer biology[7,8,9,10,11,12,13,14,15,16,17,18,19] Using this approach, disparate targets have been proposed to be responsible for nitroxoline anticancer effects. The results of this study show that the majority of proteins affected by nitroxoline treatment are interconnected in a highly enriched network of protein-protein interactions This integrative study shows that nitroxoline modulates a number of proteins and pathways crucial in cancer biology, which were previously unknown to be deregulated by this drug
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