title: Statin-induced mevalonate pathway inhibition attenuates the growth of mesenchymal-like cancer cells that lack functional E-cadherin mediated cell cohesion.
abstract: The cholesterol reducing drugs, statins, exhibit anti-tumor effects against cancer stem cells and various cancer cell lines, exert potent additivity or synergy with existing chemotherapeutics in animal models of cancer and may reduce cancer incidence and cancer related mortality in humans. However, not all tumor cell lines are sensitive to statins, and clinical trials have demonstrated mixed outcomes regarding statins as anticancer agents. Here, we show that statin-induced reduction in intracellular cholesterol levels correlate with the growth inhibition of cancer cell lines upon statin treatment. Moreover, statin sensitivity segregates with abundant cytosolic vimentin expression and absent cell surface E-cadherin expression, a pattern characteristic of mesenchymal-like cells. Exogenous expression of cell surface E-cadherin converts statin- sensitive cells to a partially resistant state implying that statin resistance is in part dependent on the tumor cells attaining an epithelial phenotype. As metastasizing tumor cells undergo epithelial to mesenchymal transition during the initiation of the metastatic cascade, statin therapy may represent an effective approach to targeting the cells most likely to disseminate.
authors.affiliation: Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Warita
authors.affiliation: Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Warita
authors.affiliation: Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Colin H
authors.initials: CH
authors.lastname: Beckwitt
authors.affiliation: 1] Department of Computational &Systems Biology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15260, USA [2] University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15260, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Schurdak
authors.affiliation: Department of Radiation Oncology and Center for Systems Biology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA.
authors.forename: Alexei
authors.initials: A
authors.lastname: Vazquez
authors.affiliation: Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Wells
authors.affiliation: 1] Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA [2] Department of Computational &Systems Biology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15260, USA.
authors.forename: Zoltán N
authors.initials: ZN
authors.lastname: Oltvai
mesh_terms: D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D002784:Cholesterol / Q000096:biosynthesis / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D015820:Cadherins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009363:Neoplasm Proteins; D002784:Cholesterol; D008798:Mevalonic Acid