title: Network-Based Analysis of Nutraceuticals in Human Hepatocellular Carcinomas Reveals Mechanisms of Chemopreventive Action.
abstract: Chronic inflammation is associated with the development of human hepatocellular carcinoma (HCC), an essentially incurable cancer. Anti-inflammatory nutraceuticals have emerged as promising candidates against HCC, yet the mechanisms through which they influence the cell signaling machinery to impose phenotypic changes remain unresolved. Herein we implemented a systems biology approach in HCC cells, based on the integration of cytokine release and phospoproteomic data from high-throughput xMAP Luminex assays to elucidate the action mode of prominent nutraceuticals in terms of topology alterations of HCC-specific signaling networks. An optimization algorithm based on SigNetTrainer, an Integer Linear Programming formulation, was applied to construct networks linking signal transduction to cytokine secretion by combining prior knowledge of protein connectivity with proteomic data. Our analysis identified the most probable target phosphoproteins of interrogated compounds and predicted translational control as a new mechanism underlying their anticytokine action. Induced alterations corroborated with inhibition of HCC-driven angiogenesis and metastasis.
authors.affiliation: GP Livanos and M Simou Laboratories, 1st Department of Critical Care Medicine & Pulmonary Services, Evangelismos Hospital, Medical School, University of Athens Athens, Greece.
authors.forename: M
authors.initials: M
authors.lastname: Michailidou
authors.affiliation: School of Mechanical Engineering, National Technical University of Athens Athens, Greece.
authors.forename: I N
authors.initials: IN
authors.lastname: Melas
authors.affiliation: ProtATonce Ltd Athens, Greece.
authors.forename: D E
authors.initials: DE
authors.lastname: Messinis
authors.affiliation: Max Planck Institute for Dynamics of Complex Technical Systems Magdeburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Klamt
authors.affiliation: School of Mechanical Engineering, National Technical University of Athens Athens, Greece.
authors.forename: L G
authors.initials: LG
authors.lastname: Alexopoulos
authors.affiliation: School of Chemical Engineering, National Technical University of Athens Athens, Greece.
authors.forename: F N
authors.initials: FN
authors.lastname: Kolisis
authors.affiliation: GP Livanos and M Simou Laboratories, 1st Department of Critical Care Medicine & Pulmonary Services, Evangelismos Hospital, Medical School, University of Athens Athens, Greece.
authors.forename: H
authors.initials: H
authors.lastname: Loutrari