Ciclopirox inhibits cancer cell proliferation by suppression of Cdc25A
Tao Shen1,2, Chaowei Shang1,2, Hongyu Zhou1, Yan Luo1,3, Mansoureh Barzegar1, Yoshinobu Odaka1,2, Yang Wu1,3, 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, cyclin dependent kinase, cell cycle, cell proliferation
Received: April 10, 2017 Accepted: May 21, 2017 Published: May 22, 2017
Abstract
Ciclopirox olamine (CPX), an off-patent fungicide, has recently been identified as a novel anticancer agent. However, the molecular mechanism underlying its anticancer action remains to be elucidated. Here we show that CPX inhibits cell proliferation in part by downregulating the protein level of Cdc25A in tumor cells. Our studies revealed that CPX did not significantly reduce Cdc25A mRNA level or Cdc25A protein synthesis, but remarkably promoted Cdc25A protein degradation. This resulted in inhibition of G1-cyclin dependent kinases (CDKs), as evidenced by increased inhibitory phosphorylation of G1-CDKs. Since Cdc25A degradation is tightly related to its phosphorylation status, we further examined whether CPX alters Cdc25A phosphorylation. The results showed that CPX treatment increased the phosphorylation of Cdc25A (S76 and S82), but only Cdc25A-S82A mutant was resistant to CPX-induced degradation. Furthermore, ectopic expression of Cdc25A-S82A partially conferred resistance to CPX inhibition of cell proliferation. Therefore, our findings indicate that CPX inhibits cell proliferation at least in part by promoting Cdc25A degradation.
