Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Oncology, SMALL-MOLECULE INHIBITOR, CELL-CYCLE, TUMOR-GROWTH, DNA-DAMAGE, CANCER, PLK1, MUTATION, P53, APOPTOSIS, BI-2536, Animals, Carcinoma, Cell Cycle Proteins, Cell Line, Tumor, Cell Proliferation, Cyclin B, Cyclin B1, Female, Humans, Mice, Protein Kinase Inhibitors, Protein Serine-Threonine Kinases, Proto-Oncogene Proteins, Pteridines, Thyroid Neoplasms, Tumor Suppressor Protein p53, Polo-Like Kinase 1, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, 3101 Biochemistry and cell biology, 3211 Oncology and carcinogenesis

Abstract:

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive and chemoresistant cancers. The serine/threonine kinase Polo-like kinase 1 (PLK1), a key regulator of multiple steps during mitotic progression, is highly expressed in ATC. Here, we used the BI 2536 PLK1 inhibitor on ATC and nontransformed thyroid follicular cell lines. Our data show that ATC cells are addicted to high levels of PLK1 activity for proliferation, survival, anchorage-independent growth, and tumorigenicity. On treatment with nanomolar doses of BI 2536, ATC cells progressed normally through S phase but died thereafter, directly from mitotic arrest. Immunofluorescence microscopy, immunoblot, and flow cytometry analysis showed that, on PLK1 blockade, ATC cells arrested in prometaphase with a 4N DNA content. Treated ATC cells accumulated phosphohistone H3 and displayed characteristic mitotic (Polo) spindle aberrations. Nontransformed thyroid cells were 3.2- to 18.4-fold less susceptible to BI 2536-induced cell cycle effects compared with ATC cells. These findings identify PLK1 as a promising target for the molecular therapy of ATC.