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Open AccessArticle

Co-Inhibition of the DNA Damage Response and CHK1 Enhances Apoptosis of Neuroblastoma Cells

1
Department of Clinical Diagnostic Oncology, Showa University Clinical Research Institute for Clinical Pharmacology and Therapeutics, 6-11-11 kita-karasuyama, setagaya-ku, Tokyo 157-8577, Japan
2
Department of Biomedical Sciences, Division of Biochemistry, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
3
Chiba Cancer Center Research Institute, Chiba 260-8717, Japan
4
Division of Molecular Medicine, Life Science Research Institute, Saga Medical Center Koseikan, Saga 840-8571, Japan
5
SAGA HIMAT Foundation, Saga 841-0071, Japan
6
Department of Pediatric Surgery, Nihon University School of Medicine, Tokyo 173-8610, Japan
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(15), 3700; https://doi.org/10.3390/ijms20153700
Received: 1 July 2019 / Revised: 22 July 2019 / Accepted: 23 July 2019 / Published: 29 July 2019
(This article belongs to the Special Issue Kinase Signal Transduction 2019)
Checkpoint kinase 1 (CHK1) is a central mediator of the DNA damage response (DDR) at the S and G2/M cell cycle checkpoints, and plays a crucial role in preserving genomic integrity. CHK1 overexpression is thought to contribute to cancer aggressiveness, and several selective inhibitors of this kinase are in clinical development for various cancers, including neuroblastoma (NB). Here, we examined the sensitivity of MYCN-amplified NB cell lines to the CHK1 inhibitor PF-477736 and explored mechanisms to increase its efficacy. PF-477736 treatment of two sensitive NB cell lines, SMS-SAN and CHP134, increased the expression of two pro-apoptotic proteins, BAX and PUMA, providing a mechanism for the effect of the CHK1 inhibitor. In contrast, in NB-39-nu and SK-N-BE cell lines, PF-477736 induced DNA double-strand breaks and activated the ataxia telangiectasia mutated serine/threonine kinase (ATM)-p53-p21 axis of the DDR pathway, which rendered the cells relatively insensitive to the antiproliferative effects of the CHK1 inhibitor. Interestingly, combined treatment with PF-477736 and the ATM inhibitor Ku55933 overcame the insensitivity of NB-39-nu and SK-N-BE cells to CHK1 inhibition and induced mitotic cell death. Similarly, co-treatment with PF-477736 and NU7441, a pharmacological inhibitor of DNA-PK, which is also essential for the DDR pathway, rendered the cells sensitive to CHK1 inhibition. Taken together, our results suggest that synthetic lethality between inhibitors of CHK1 and the DDR drives G2/M checkpoint abrogation and could be a novel potential therapeutic strategy for NB. View Full-Text
Keywords: CHK1; ATM; DNA-PK; neuroblastoma; checkpoint abrogation CHK1; ATM; DNA-PK; neuroblastoma; checkpoint abrogation
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MDPI and ACS Style

Ando, K.; Nakamura, Y.; Nagase, H.; Nakagawara, A.; Koshinaga, T.; Wada, S.; Makishima, M. Co-Inhibition of the DNA Damage Response and CHK1 Enhances Apoptosis of Neuroblastoma Cells. Int. J. Mol. Sci. 2019, 20, 3700. https://doi.org/10.3390/ijms20153700

AMA Style

Ando K, Nakamura Y, Nagase H, Nakagawara A, Koshinaga T, Wada S, Makishima M. Co-Inhibition of the DNA Damage Response and CHK1 Enhances Apoptosis of Neuroblastoma Cells. International Journal of Molecular Sciences. 2019; 20(15):3700. https://doi.org/10.3390/ijms20153700

Chicago/Turabian Style

Ando, Kiyohiro; Nakamura, Yohko; Nagase, Hiroki; Nakagawara, Akira; Koshinaga, Tsugumichi; Wada, Satoshi; Makishima, Makoto. 2019. "Co-Inhibition of the DNA Damage Response and CHK1 Enhances Apoptosis of Neuroblastoma Cells" Int. J. Mol. Sci. 20, no. 15: 3700. https://doi.org/10.3390/ijms20153700

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