Selective pharmacologic inhibition of c-Jun NH2-terminal kinase radiosensitizes thyroid anaplastic cancer cell lines via induction of terminal growth arrest.

Context: The high radioresistance of anaplastic thyroid cancer (ATC) and cultured ATC cells stipulates for the means of increasing their radiosensitivity. It has been shown that c-Jun NH(2)-terminal kinase (JNK) activation is one of the manifestations of radiation response in ATC cells.

Objective: Assessment of the effect of selective JNK inhibition on ATC cell radiosensitivity and clarification of the associated mechanisms.

Results: The JNK inhibitor markedly suppressed ATC cell growth in a reversible cytostatic manner. The combination treatment with JNK inhibitor plus ionizing radiation induced a significant decrease in clonogenic survival of irradiated cells as compared with either singular treatment. The effect was not due to apoptosis of exposed cells but to a profound senescence-like terminal growth arrest occurring irrespectively of cells' p53 mutational status. Postradiational DNA damage repair was also significantly compromised in the presence of SP600125.

Conclusions: JNK signaling is an essential component of ATC cell proliferation and survival after radiation therapy. Hence, pharmacological interference with JNK pathway in combination with radiotherapy may be a promising treatment of ATC.