Identification of Polo-like Kinase 1 as a Potential Therapeutic Target in Anaplastic Thyroid Carcinoma

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 nontransfo...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2009-03, Vol.69 (5), p.1916-1923
Main Authors: CLAUDIO NAPPI, Tito, SALERNO, Paolo, ZITZELSBERGER, Horst, CARLOMAGNO, Francesca, SALVATORE, Giuliana, SANTORO, Massimo
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Biological and medical sciences
Carcinoma - drug therapy
Carcinoma - pathology
Cell Cycle Proteins - antagonists & inhibitors
Cell Line, Tumor
Cell Proliferation - drug effects
Cyclin B - analysis
Cyclin B1
Endocrinopathies
Female
Humans
Malignant tumors
Medical sciences
Mice
Non tumoral diseases. Target tissue resistance. Benign neoplasms
Pharmacology. Drug treatments
Polo-Like Kinase 1
Protein Kinase Inhibitors - pharmacology
Protein Serine-Threonine Kinases - antagonists & inhibitors
Proto-Oncogene Proteins - antagonists & inhibitors
Pteridines - pharmacology
Thyroid Neoplasms - drug therapy
Thyroid Neoplasms - pathology
Thyroid. Thyroid axis (diseases)
Tumor Suppressor Protein p53 - physiology
Tumors
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-08-1693