Grassi Elisa Stellaria, Vezzoli Valeria, Negri Irene, Lábadi Árpád, Fugazzola Laura, Vitale Giovanni, Persani Luca
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.
Oncotarget. 2015 Nov 3;6(34):36383-99. doi: 10.18632/oncotarget.5799.
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.
甲状腺癌是最常见的内分泌恶性肿瘤，在全球范围内发病率不断上升。大多数甲状腺癌病例分化良好，预后良好。然而，未分化甲状腺癌是最致命的人类恶性肿瘤之一，因为它们具有侵袭性、转移性，甚至对最新开发的治疗方法也具有耐药性。在本研究中，我们首次发现甲状腺癌组织中ROCK/HDAC6通路显著过度激活，且其与p53 DNA结合能力呈负相关。我们证明，一种小分子化合物SP600125（SP）能够通过特异性作用于癌症发展的致病途径，在未分化甲状腺癌细胞系中选择性诱导细胞死亡。具体而言，SP作用于参与未分化人类癌症去分化和侵袭的ROCK/HDAC6通路，恢复其生理活性水平。主要结果是，癌细胞迁移受到抑制，同时通过有丝分裂灾难诱导细胞死亡。此外，SP通过增加其DNA结合能力，对突变型p53发挥优先作用。在经历有丝分裂灾难后存活的TP53突变细胞中，这一过程导致p21诱导，最终导致早衰。总之，SP已被证明能够同时阻断细胞复制和迁移，这是癌症发展和扩散所涉及的两个主要过程，使其成为开发抗间变性甲状腺癌新药的理想候选药物。
