The potent inhibitor of the cell cycle checkpoint regulatory factor Wee-1, MK-1775, has been reported to enhance non-small cell lung cancer (NSCLC) cell sensitivity to photon radiation by abrogating radiation-induced G2 arrest. However, little is known about the effects of this sensitizer after exposure to carbon (C)-ion radiation. The purpose of this study was therefore to investigate the effects of C ions in combination with MK-1775 on the killing of NSCLC cells. Human NSCLC H1299 cells were exposed to X rays or C ions (290 MeV/n, 50 keV/μm at the center of a 6 cm spread-out Bragg peak) in the presence of MK-1775. The cell cycle was analyzed using flow cytometry and Western blotting. Radiosensitivity was determined using clonogenic survival assays. The mechanisms underlying MK-1775 radiosensitization were studied by observing H2AX phosphorylation and mitotic catastrophe. G2 checkpoint arrest was enhanced 2.3-fold by C-ion exposure compared with X-ray exposure. Radiation-induced G2 checkpoint arrest was abrogated by MK-1775. Exposure to radiation resulted in a significant reduction in the mitotic ratio and increased phosphorylation of cyclin-dependent kinase 1 (Cdk1), the primary downstream mediator of Wee-1-induced G2 arrest. The Wee-1 inhibitor, MK-1775 restored the mitotic ratio and suppressed Cdk1 phosphorylation. In addition, MK-1775 increased H1299 cell sensitivity to C ions and X rays independent of TP53 status. MK-1775 also significantly increased H2AX phosphorylation and mitotic catastrophe in irradiated cells. These results suggest that the G2 checkpoint inhibitor MK-1775 can enhance the sensitivity of human NSCLC cells to C ions as well as X rays.
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1 December 2015
Research Article|
December 04 2015
Targeting of Carbon Ion-Induced G2 Checkpoint Activation in Lung Cancer Cells Using Wee-1 Inhibitor MK-1775
Hongyu Ma
;
Hongyu Ma
a Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Japan; and
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Akihisa Takahashi
;
Akihisa Takahashi
1
b Gunma University Heavy Ion Medical Center, Maebashi, Japan
1 Address for correspondence: Gunma University Heavy Ion Medical Center, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan; email: a-takahashi@gunma-u.ac.jp.
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Yukihiko Sejimo
;
Yukihiko Sejimo
b Gunma University Heavy Ion Medical Center, Maebashi, Japan
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Akiko Adachi
;
Akiko Adachi
a Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Japan; and
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Nobuteru Kubo
;
Nobuteru Kubo
a Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Japan; and
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Mayu Isono
;
Mayu Isono
b Gunma University Heavy Ion Medical Center, Maebashi, Japan
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Yukari Yoshida
;
Yukari Yoshida
b Gunma University Heavy Ion Medical Center, Maebashi, Japan
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Tatsuaki Kanai
;
Tatsuaki Kanai
b Gunma University Heavy Ion Medical Center, Maebashi, Japan
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Tatsuya Ohno
;
Tatsuya Ohno
b Gunma University Heavy Ion Medical Center, Maebashi, Japan
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Takashi Nakano
Takashi Nakano
a Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Japan; and
b Gunma University Heavy Ion Medical Center, Maebashi, Japan
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Radiat Res (2015) 184 (6): 660–669.
Article history
Received:
June 15 2015
Accepted:
September 30 2015
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Citation
Hongyu Ma, Akihisa Takahashi, Yukihiko Sejimo, Akiko Adachi, Nobuteru Kubo, Mayu Isono, Yukari Yoshida, Tatsuaki Kanai, Tatsuya Ohno, Takashi Nakano; Targeting of Carbon Ion-Induced G2 Checkpoint Activation in Lung Cancer Cells Using Wee-1 Inhibitor MK-1775. Radiat Res 1 December 2015; 184 (6): 660–669. doi: https://doi.org/10.1667/RR14171.1
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