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Integrative proteomic and functional analyses provide novel insights into the action of the repurposed drug candidate nitroxoline in AsPC-1 cells.

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 ?-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.

SUBMITTER: Veschi S

PROVIDER: S-EPMC7018951 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Integrative proteomic and functional analyses provide novel insights into the action of the repurposed drug candidate nitroxoline in AsPC-1 cells.

Veschi Serena S Ronci Maurizio M Lanuti Paola P De Lellis Laura L Florio Rosalba R Bologna Giuseppina G Scotti Luca L Carletti Erminia E Brugnoli Federica F Di Bella Maria Cristina MC Bertagnolo Valeria V Marchisio Marco M Cama Alessandro A

Scientific reports 20200213 1

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 ...[more]

PMID: 32054977

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Project description:Somatic embryogenesis (SE) is an ideal model for plant cell totipotency. Transition from somatic cells to embryogenic cells is the key to SE. The poor frequency of embryogenic callus (EC) induction has limited the application of SE in many plants, such as Agapanthus praecox. We performed large-scale, quantitative proteomic and metabolomic analyses with different callus differentiation directions (SE and organogenesis) and stages (initial SE and repetitive SE) to better understand the morphological, physiological, and molecular characteristics of the acquisition of embryogenic ability in A. praecox. Integrated proteomic and metabolomic analyses suggested that callus differentiation direction was potentially regulated by pathways related to carbohydrate and energy metabolism (fatty acid metabolism, pyruvate metabolism, glycolysis/gluconeogenesis, pentose and glucuronate interconversions, starch and sucrose metabolism, galactose metabolism, carbon fixation pathways in prokaryotes, carbohydrate digestion and absorption, and fructose and mannose metabolism), chromatin accessibility and DNA methylation, reactive oxygen species responses and resistance (ascorbate and aldarate metabolism), and plant hormonal signaling. As a validation, we found that carbon source combination and plant hormone regulation in the culture medium significantly affected the acquisition of embryogenic ability, thereby inducing EC. Interestingly, plant hormonal signaling-related genes showed different expression patterns significantly when callus cultured with different carbon sources. Thus, our results suggested that energy supply and hormone signal transduction seemed to cooperatively contribute to the activation of embryogenic ability. Altogether, this study revealed valuable information regarding the molecular and biochemical changes that occurred during EC induction and provided valuable foundation for comprehensive understanding of the mechanisms associated with SE and organogenesis in A. praecox.

Dataset Information

Integrative proteomic and functional analyses provide novel insights into the action of the repurposed drug candidate nitroxoline in AsPC-1 cells.

Publications

Integrative proteomic and functional analyses provide novel insights into the action of the repurposed drug candidate nitroxoline in AsPC-1 cells.

Similar Datasets

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