SP600125 has a remarkable anticancer potential against undifferentiated thyroid cancer through selective action on ROCK and p53 pathways
| Autor: | Árpád Lábadi, Irene Negri, Giovanni Vitale, Valeria Vezzoli, Laura Fugazzola, Elisa Stellaria Grassi, Luca Persani |
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| Rok vydání: | 2015 |
| Předmět: |
p53
Histone Deacetylase 6 Thyroid cancer Histone Deacetylases Cell Line Tumor ROCK medicine thyroid cancer Endocrine system Humans Thyroid Neoplasms Anaplastic thyroid cancer Mitotic catastrophe Protein Kinase Inhibitors mitotic catastrophe Cell Proliferation Anthracenes P53 rho-Associated Kinases SP600125 Cell growth business.industry Thyroid Cell cycle medicine.disease Transplantation medicine.anatomical_structure Oncology Immunology Cancer research Tumor Suppressor Protein p53 business Psychiatrie Signal Transduction Research Paper |
| Zdroj: | Oncotarget Oncotarget, 6 (34 |
| ISSN: | 1949-2553 |
| Popis: | 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. SCOPUS: ar.j info:eu-repo/semantics/published |
| Databáze: | OpenAIRE |
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