title: Nuclear lipid microdomain as resting place of dexamethasone to impair cell proliferation.
abstract: The action of dexamethasone is initiated by, and strictly dependent upon, the interaction of the drug with its receptor followed by its translocation into the nucleus where modulates gene expression. Where the drug localizes at the intranuclear level is not yet known. We aimed to study the localization of the drug in nuclear lipid microdomains rich in sphingomyelin content that anchor active chromatin and act as platform for transcription modulation. The study was performed in non-Hodgkin's T cell human lymphoblastic lymphoma (SUP-T1 cell line). We found that when dexamethasone enters into the nucleus it localizes in nuclear lipid microdomains where influences sphingomyelin metabolism. This is followed after 24 h by a cell cycle block accompanied by the up-regulation of cyclin-dependent kinase inhibitor 1A (CDKN1A), cyclin-dependent kinase inhibitor 1B (CDKN1B), growth arrest and DNA-damage 45A (GADD45A), and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) genes and by the reduction of signal transducer and activator of transcription 3 (STAT3) and phospho signal transducer and activator of transcription 3 (phoshoSTAT3) proteins. After 48 h some cells show morphological changes characteristic of apoptosis while the number of the cells that undergo cell division and express B-cell lymphoma-2 (Bcl-2) is very low. We suggest that the integrity of nuclear lipid microdomains is important for the response to glucocorticoids of cancer cells.
authors.affiliation: Laboratory of Nuclear Lipid BioPathology, Crabion, 06074 Perugia, Italy. samuelacataldi@libero.it.
authors.forename: Samuela
authors.initials: S
authors.lastname: Cataldi
authors.affiliation: Department of Pharmaceutical Science, University of Perugia, 06100 Perugia, Italy. codini@virgilio.it.
authors.forename: Michela
authors.initials: M
authors.lastname: Codini
authors.affiliation: Laboratory of Nuclear Lipid BioPathology, Crabion, 06074 Perugia, Italy. giacomocascianelli@tiscali.it.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Cascianelli
authors.affiliation: Laboratory of Clinical Pathology, 96011 Augusta-Siracusa, Italy. info@lab-tringali-s.com.
authors.forename: Sabina
authors.initials: S
authors.lastname: Tringali
authors.affiliation: Laboratory of Clinical Pathology, 96011 Augusta-Siracusa, Italy. annatringali69@gmail.com.
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Tringali
authors.affiliation: Laboratory of Nuclear Lipid BioPathology, Crabion, 06074 Perugia, Italy. andrylazza@gmail.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Lazzarini
authors.affiliation: Laboratory of Nuclear Lipid BioPathology, Crabion, 06074 Perugia, Italy. info@crabion.it.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Floridi
authors.affiliation: Laboratory of Nuclear Lipid BioPathology, Crabion, 06074 Perugia, Italy. infoe@crabion.it.
authors.forename: Elisa
authors.initials: E
authors.lastname: Bartoccini
authors.affiliation: Department of Biology, University of Pisa, 56127 Pisa, Italy. mercedes.garcia@unipi.it.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Garcia-Gil
authors.affiliation: Laboratory of Nuclear Lipid BioPathology, Crabion, 06074 Perugia, Italy. remo30@libero.it.
authors.forename: Remo
authors.initials: R
authors.lastname: Lazzarini
authors.affiliation: Department of Clinical and Biological Sciences, University of Udine, 33100 Udine, Italy. ambesis@me.com.
authors.forename: Francesco Saverio
authors.initials: FS
authors.lastname: Ambesi-Impiombato
authors.affiliation: Department of Clinical and Biological Sciences, University of Udine, 33100 Udine, Italy. curcio@uniud.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Curcio
authors.affiliation: Department of Pharmaceutical Science, University of Perugia, 06100 Perugia, Italy. tommaso.beccari@unipg.it.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Beccari
authors.affiliation: Laboratory of Nuclear Lipid BioPathology, Crabion, 06074 Perugia, Italy. elisabetta.albi@yahoo.com.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Albi
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects*; D002843:Chromatin / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+) / Q000235:genetics / Q000378:metabolism; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013109:Sphingomyelins / Q000378:metabolism; D017855:Transferases (Other Substituted Phosphate Groups) / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D000097642:GADD45 Proteins
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003907:Dexamethasone; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+); D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; D013108:Sphingomyelin Phosphodiesterase; D013109:Sphingomyelins; D017855:Transferases (Other Substituted Phosphate Groups); C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C070186:phosphatidylcholine-ceramide phosphocholine transferase