Selective pharmacologic inhibition of c-Jun NH2-terminal kinase radiosensitizes thyroid anaplastic cancer cell lines via induction of terminal growth arrest.
BACKGROUND
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.
Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
Dmitry
D
Bulgin
Alexei
A
Podtcheko
Shu
S
Takakura
Norisato
N
Mitsutake
Hiroyuki
H
Namba
Vladimir
V
Saenko
Akira
A
Ohtsuru
Tatiana
T
Rogounovitch
Iryna
I
Palona
Shunichi
S
Yamashita
D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000873:Anthracenes / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D003131:Combined Modality Therapy; D004260:DNA Repair / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000502:physiology; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D000873:Anthracenes; D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases