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Camptothecin induces G2/M phase arrest through the ATM-Chk2-Cdc25C axis as a result of autophagy-induced cytoprotection: Implications of reactive oxygen species
| Content Provider | Semantic Scholar |
|---|---|
| Author | Jayasooriya, Rajapaksha Gedara Prasad Tharanga Dilshara, Matharage Gayani Molagoda, Ilandarage Menu Neelaka Park, Cheol Park, Sang Rul Lee, Seungheon Choi, Young Hyun Kim, Gi Young |
| Copyright Year | 2018 |
| Abstract | 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. |
| Starting Page | 21744 |
| Ending Page | 21757 |
| Page Count | 14 |
| File Format | PDF HTM / HTML |
| PubMed reference number | 29774099v1 |
| Alternate Webpage(s) | https://doi.org/10.18632/oncotarget.24934 |
| DOI | 10.18632/oncotarget.24934 |
| Journal | Oncotarget |
| Volume Number | 9 |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Apoptosis Ataxia Telangiectasia Autophagy Axis vertebra Camptothecin Cell Cycle Arrest Cell division Cyclin B1 Cytoprotection Episodic ataxia type 2 (disorder) Genus Axis Glutathione Leukemia, B-Cell MG 132 Moderate Response Negative Regulation of Mitosis Negative Regulation of S Phase Reactive Oxygen Species Sex Factors Telangiectasis eIF-2 Kinase |
| Content Type | Text |
| Resource Type | Article |
