title: Translational downregulation of HSP90 expression by iron chelators in neuroblastoma cells.
abstract: Iron is an essential cellular nutrient, being a critical cofactor of several proteins involved in cell growth and replication. Compared with normal cells, neoplastic cells have been shown to require a greater amount of iron, thus laying the basis for the promising anticancer activity of iron chelators. In this work, we evaluated the effects of molecules with iron chelation activity on neuroblastoma (NB) cell lines. Of the 17 iron chelators tested, six reduced cell viability of two NB cell lines with an inhibition of growth of 50% below 10 µM; four of the six molecules-ciclopirox olamine (CPX), piroctone, 8-hydroxyquinoline, and deferasirox-were also shown to efficiently chelate intracellular iron within minutes after addition. Effects on cell viability of one of the compounds, CPX, were indeed dependent on chelation of intracellular iron and mediated by both G0/G1 cell cycle block and induction of apoptosis. By combined transcriptome and translatome profiling we identified early translational downregulation of several members of the heat shock protein group as a specific effect of CPX treatment. We functionally confirmed iron-dependent depletion of HSP90 and its client proteins at pharmacologically achievable concentrations of CPX, and we extended this effect to piroctone, 8-hydroxyquinoline, and deferasirox. Given the documented sensitivity of NB cells to HSP90 inhibition, we propose CPX and other iron chelators as investigational antitumor agents in NB therapy.
authors.affiliation: Laboratory of Translational Genomics, Centre for Integrative Biology, University of Trento, Trento, Italy (V.S., P.G., V.G., T.T., A.Q.); High-Throughput Screening Core Facility, Centre for Integrative Biology, University of Trento, Trento, Italy (V.A.); and Neuroblastoma Laboratory, Onco/Hematology Laboratory, SDB Department, University of Padua, Pediatric Research Institute, Padua, Italy (G.P.T.) viktoryia.sidarovich@unitn.it alessandro.quattrone@unitn.it.
authors.forename: Viktoryia
authors.initials: V
authors.lastname: Sidarovich
authors.affiliation: Laboratory of Translational Genomics, Centre for Integrative Biology, University of Trento, Trento, Italy (V.S., P.G., V.G., T.T., A.Q.); High-Throughput Screening Core Facility, Centre for Integrative Biology, University of Trento, Trento, Italy (V.A.); and Neuroblastoma Laboratory, Onco/Hematology Laboratory, SDB Department, University of Padua, Pediatric Research Institute, Padua, Italy (G.P.T.).
authors.forename: Valentina
authors.initials: V
authors.lastname: Adami
authors.affiliation: Laboratory of Translational Genomics, Centre for Integrative Biology, University of Trento, Trento, Italy (V.S., P.G., V.G., T.T., A.Q.); High-Throughput Screening Core Facility, Centre for Integrative Biology, University of Trento, Trento, Italy (V.A.); and Neuroblastoma Laboratory, Onco/Hematology Laboratory, SDB Department, University of Padua, Pediatric Research Institute, Padua, Italy (G.P.T.).
authors.forename: Pamela
authors.initials: P
authors.lastname: Gatto
authors.affiliation: Laboratory of Translational Genomics, Centre for Integrative Biology, University of Trento, Trento, Italy (V.S., P.G., V.G., T.T., A.Q.); High-Throughput Screening Core Facility, Centre for Integrative Biology, University of Trento, Trento, Italy (V.A.); and Neuroblastoma Laboratory, Onco/Hematology Laboratory, SDB Department, University of Padua, Pediatric Research Institute, Padua, Italy (G.P.T.).
authors.forename: Valentina
authors.initials: V
authors.lastname: Greco
authors.affiliation: Laboratory of Translational Genomics, Centre for Integrative Biology, University of Trento, Trento, Italy (V.S., P.G., V.G., T.T., A.Q.); High-Throughput Screening Core Facility, Centre for Integrative Biology, University of Trento, Trento, Italy (V.A.); and Neuroblastoma Laboratory, Onco/Hematology Laboratory, SDB Department, University of Padua, Pediatric Research Institute, Padua, Italy (G.P.T.).
authors.forename: Toma
authors.initials: T
authors.lastname: Tebaldi
authors.affiliation: Laboratory of Translational Genomics, Centre for Integrative Biology, University of Trento, Trento, Italy (V.S., P.G., V.G., T.T., A.Q.); High-Throughput Screening Core Facility, Centre for Integrative Biology, University of Trento, Trento, Italy (V.A.); and Neuroblastoma Laboratory, Onco/Hematology Laboratory, SDB Department, University of Padua, Pediatric Research Institute, Padua, Italy (G.P.T.).
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Tonini
authors.affiliation: Laboratory of Translational Genomics, Centre for Integrative Biology, University of Trento, Trento, Italy (V.S., P.G., V.G., T.T., A.Q.); High-Throughput Screening Core Facility, Centre for Integrative Biology, University of Trento, Trento, Italy (V.A.); and Neuroblastoma Laboratory, Onco/Hematology Laboratory, SDB Department, University of Padua, Pediatric Research Institute, Padua, Italy (G.P.T.) viktoryia.sidarovich@unitn.it alessandro.quattrone@unitn.it.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Quattrone
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D006367:HeLa Cells; D006801:Humans; D007502:Iron Chelating Agents / Q000494:pharmacology*; D061986:MCF-7 Cells; D009447:Neuroblastoma / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology*
chemical_list: D018841:HSP90 Heat-Shock Proteins; D007502:Iron Chelating Agents