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.