title: SP600125 has a remarkable anticancer potential against undifferentiated thyroid cancer through selective action on ROCK and p53 pathways.
abstract: Thyroid cancer is the most common endocrine malignancy with increasing incidence worldwide.The majority of thyroid cancer cases are well differentiated with favorable outcome. However, undifferentiated thyroid cancers are one of the most lethal human malignancies because of their invasiveness, metastatization and refractoriness even to the most recently developed therapies.In this study we show for the first time a significant hyperactivation of ROCK/HDAC6 pathway in thyroid cancer tissues, and its negative correlation with p53 DNA binding ability.We demonstrate that a small compound, SP600125 (SP), is able to induce cell death selectively in undifferentiated thyroid cancer cell lines by specifically acting on the pathogenic pathways of cancer development. In detail, SP acts on the ROCK/HDAC6 pathway involved in dedifferentiation and invasiveness of undifferentiated human cancers, by restoring its physiological activity level. As main consequence, cancer cell migration is inhibited and, at the same time, cell death is induced through the mitotic catastrophe. Moreover, SP exerts a preferential action on the mutant p53 by increasing its DNA binding ability. In TP53-mutant cells that survive mitotic catastrophe this process results in p21 induction and eventually lead to premature senescence. In conclusion, SP has been proved to be able to simultaneously block cell replication and migration, the two main processes involved in cancer development and dissemination, making it an ideal candidate for developing new drugs against anaplastic thyroid cancer.
authors.affiliation: DISCCO, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
authors.forename: Elisa Stellaria
authors.initials: ES
authors.lastname: Grassi
authors.affiliation: DISCCO, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Vezzoli
authors.affiliation: Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS, Cusano Milanino, Italy.|Current address: IRIBHM, Institute of Interdisciplinary Research in Molecular Human Biology, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Irene
authors.initials: I
authors.lastname: Negri
authors.affiliation: Department of Laboratory Medicine, University of Pécs, Pécs, Hungary.
authors.forename: Árpád
authors.initials: Á
authors.lastname: Lábadi
authors.affiliation: Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.|Endocrine Unit-Fondazione IRCCS Ca' Granda, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Fugazzola
authors.affiliation: DISCCO, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.|Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS, Cusano Milanino, Italy.|Division of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Vitale
authors.affiliation: DISCCO, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.|Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS, Cusano Milanino, Italy.|Division of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Persani
mesh_terms: D000873:Anthracenes / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D000873:Anthracenes; D047428:Protein Kinase Inhibitors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C432165:pyrazolanthrone; D054460:rho-Associated Kinases; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: ROCK; SP600125; mitotic catastrophe; p53; thyroid cancer