title: Nano-ZnO leads to tubulin macrotube assembly and actin bundling, triggering cytoskeletal catastrophe and cell necrosis.
abstract: Zinc is a crucial element in biology that plays chief catalytic, structural and protein regulatory roles. Excess cytoplasmic zinc is toxic to cells so there are cell-entry and intracellular buffering mechanisms that control intracellular zinc availability. Tubulin and actin are two zinc-scavenging proteins that are essential components of the cellular cytoskeleton implicated in cell division, migration and cellular architecture maintenance. Here we demonstrate how exposure to different ZnO nanostructures, namely ZnO commercial nanoparticles and custom-made ZnO nanowires, produce acute cytotoxic effects in human keratinocytes (HaCat) and epithelial cells (HeLa) triggering a dose-dependent cell retraction and collapse. We show how engulfed ZnO nanoparticles dissolve intracellularly, triggering actin filament bundling and structural changes in microtubules, transforming these highly dynamic 25 nm diameter polymers into rigid macrotubes of tubulin, severely affecting cell proliferation and survival. Our results demonstrate that nano-ZnO causes acute cytoskeletal collapse that triggers necrosis, followed by a late reactive oxygen species (ROS)-dependent apoptotic process.
authors.affiliation: Grupo de Nanomedicina-IDIVAL, Facultad de Medicina, Herrera Oria s/n, 39011 Santander, Spain. fanarrag@unican.es.
authors.forename: Lorena
authors.initials: L
authors.lastname: García-Hevia
authors.forename: Rafael
authors.initials: R
authors.lastname: Valiente
authors.forename: Rosa
authors.initials: R
authors.lastname: Martín-Rodríguez
authors.forename: Carlos
authors.initials: C
authors.lastname: Renero-Lecuna
authors.forename: Jesús
authors.initials: J
authors.lastname: González
authors.forename: Lidia
authors.initials: L
authors.lastname: Rodríguez-Fernández
authors.forename: Fernando
authors.initials: F
authors.lastname: Aguado
authors.forename: Juan C
authors.initials: JC
authors.lastname: Villegas
authors.forename: Mónica L
authors.initials: ML
authors.lastname: Fanarraga
mesh_terms: D000199:Actins / Q000737:chemistry*; D017209:Apoptosis; D002470:Cell Survival; D003599:Cytoskeleton / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D015603:Keratinocytes / Q000166:cytology*; D053768:Metal Nanoparticles; D009336:Necrosis; D017382:Reactive Oxygen Species / Q000378:metabolism; D014404:Tubulin / Q000737:chemistry*; D015034:Zinc Oxide
chemical_list: D000199:Actins; D017382:Reactive Oxygen Species; D014404:Tubulin; D015034:Zinc Oxide