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Camptothecin induces G 2 / M phase arrest through the ATM-Chk 2-Cdc 25 C 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 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 CPTinduced 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-ATMChk2-Cdc25C axis is accompanied by the activation of autophagy. www.oncotarget.com Oncotarget, 2018, Vol. 9, (No. 31), pp: 21744-21757 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://www.oncotarget.com/index.php?journal=oncotarget&op=download&page=article&path%5B%5D=24934&path%5B%5D=78175 |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
