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 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.
Nappi
Tito Claudio
TC
Dipartimento di Biologia e Patologia Cellulare e Molecolare L. Califano c/o Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Universita' Federico II, Naples, Italy.
Salerno
Paolo
P
Zitzelsberger
Horst
H
Carlomagno
Francesca
F
Salvatore
Giuliana
G
Santoro
Massimo
M
D000818:Animals; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019926:Cyclin B / Q000032:analysis; D056744:Cyclin B1; D005260:Female; D006801:Humans; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D011621:Pteridines / Q000494:pharmacology*; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D000097869:Polo-Like Kinase 1
D018797:Cell Cycle Proteins; D019926:Cyclin B; D056744:Cyclin B1; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D016159:Tumor Suppressor Protein p53; D000097869:Polo-Like Kinase 1; C518477:BI 2536; C534699:CCNB1 protein, human; C534700:Ccnb1 protein, mouse