Research Papers:

Camptothecin induces G2/M phase arrest through the ATM-Chk2-Cdc25C axis as a result of autophagy-induced cytoprotection: Implications of reactive oxygen species

Rajapaksha Gedara Prasad Tharanga Jayasooriya, Matharage Gayani Dilshara, Ilandarage Menu Neelaka Molagoda, Cheol Park, Sang Rul Park, Seungheon Lee, Yung Hyun Choi _ and Gi-Young Kim

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Oncotarget. 2018; 9:21744-21757. https://doi.org/10.18632/oncotarget.24934

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Rajapaksha Gedara Prasad Tharanga Jayasooriya1,4, Matharage Gayani Dilshara1, Ilandarage Menu Neelaka Molagoda1, Cheol Park2, Sang Rul Park1, Seungheon Lee1, Yung Hyun Choi3 and Gi-Young Kim1

1Department of Marine Life Sciences, Jeju National University, Jeju 63243, Republic of Korea

2Department of Molecular Biology, College of Natural Sciences and Human Ecology, Dongeui University, Busan 47340, Republic of Korea

3Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan 47227, Republic of Korea

4Present address: Department of Bioprocess Technology, Faculty of Technology, University of Rajarata, Mihintale 50300, Sri Lanka

Correspondence to:

Yung Hyun Choi, email: [email protected]

Gi-Young Kim, email: [email protected]

Keywords: camptothecin; G2/M phase arrest; ROS; ATM; Chk2

Received: May 23, 2016     Accepted: February 28, 2018     Published: April 24, 2018


In the present study, we report that camptothecin (CPT) caused irreversible cell cycle arrest at the G2/M phase, and was associated with decreased levels of cell division cycle 25C (Cdc25C) and increased levels of cyclin B1, p21, and phospho-H3. Interestingly, the reactive oxygen species (ROS) inhibitor, glutathione, decreased CPT-induced G2/M phase arrest and moderately induced S phase arrest, indicating that the ROS is required for the regulation of CPT-induced G2/M phase arrest. Furthermore, transient knockdown of nuclear factor-erythroid 2-related factor 2 (Nrf2), in the presence of CPT, increased the ROS’ level and further shifted the cell cycle from early S phase to the G2/M phase, indicating that Nrf2 delayed the S phase in response to CPT. We also found that CPT-induced G2/M phase arrest increased, along with the ataxia telangiectasia-mutated (ATM)-checkpoint kinase 2 (Chk2)-Cdc25C axis. Additionally, the proteasome inhibitor, MG132, restored the decrease in Cdc25C levels in response to CPT, and significantly downregulated CPT-induced G2/M phase arrest, suggesting that CPT enhances G2/M phase arrest through proteasome-mediated Cdc25C degradation. Our data also indicated that inhibition of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) inhibited CPT-induced p21 and cyclin B1 levels; however, inhibition of ERK blocked CPT-induced G2/M phase arrest, and inhibition of JNK enhanced apoptosis in response to CPT. Finally, we found that CPT-induced G2/M phase arrest circumvented apoptosis by activating autophagy through ATM activation. These findings suggest that CPT-induced G2/M phase arrest through the ROS-ATM-Chk2-Cdc25C axis is accompanied by the activation of autophagy.

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