Ciclopirox activates ATR-Chk1 signaling pathway leading to Cdc25A protein degradation
Tao Shen1,2, Hongyu Zhou1, Chaowei Shang1,2, Yan Luo1,3, Yang Wu1,3 and Shile Huang1,2
1 Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA
2 Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, USA
3 State Key Laboratory of Biotherapy / Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China
Correspondence:
Shile Huang, email:
Keywords: Ciclopirox; Cdc25A; ATR; Chk1; DNA damage
Received: January 08, 2018 Accepted: February 11, 2018 Published: February 15, 2018
Abstract
Ciclopirox olamine (CPX), an off-patent anti-fungal drug, has been found to inhibit the G1-cyclin dependent kinases partly by increasing the phosphorylation and degradation of Cdc25A. However, little is known about the molecular target(s) of CPX responsible for Cdc25A degradation. Here, we show that CPX induced the degradation of Cdc25A neither by increasing CK1α or decreasing DUB3 expression, nor via activating GSK3β, but through activating Chk1 in rhabdomyosarcoma (Rh30) and breast carcinoma (MDA-MB-231) cells. This is strongly supported by the findings that inhibition of Chk1 with TCS2312 or knockdown of Chk1 profoundly attenuated CPX-induced Cdc25A degradation in the cells. Furthermore, we observed that CPX caused DNA damage, which was independent of reactive oxygen species (ROS) induction, but related to iron chelation. CPX treatment resulted in the activation of ataxia telangiectasia mutated (ATM) and ATM-and RAD3-related (ATR) kinases. Treatment with Ku55933 (a selective ATM inhibitor) failed to prevent CPX-induced Chk1 phosphorylation and Cdc25A degradation. In contrast, knockdown of ATR conferred high resistance to CPX-induced Chk1 phosphorylation and Cdc25A degradation. Therefore, the results suggest that CPX-induced degradation of Cdc25A is attributed to the activation of ATR-Chk1 signaling pathway, a consequence of iron chelation-induced DNA damage.
