Ciclopirox activates ATR-Chk1 signaling pathway leading to Cdc25A protein degradation.

Tao Shen,Chaowei Shang,Yang Wu,Yan Luo,Shile Huang,Hongyu Zhou

doi:10.18632/genesandcancer.166

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.

Highlights

Ciclopirox olamine (CPX), which has a broad spectrum of action against dermatophytes, yeast, filamentous fungi and bacteria [1], has been widely used for the treatment of superficial fungal infection for over 20 years [2]
Our previous study has shown that CPX induces the phosphorylation of cell division cycle 25 A (Cdc25A) on S82, and Cdc25A-S82A mutant is resistant to CPX-induced degradation [32], indicating that the phosphorylation on S82 is essential for CPX-induced Cdc25A degradation
Since casein kinase 1α (CK1α) has been reported to be responsible for phosphorylating Cdc25A on S82 [40], and CK1α is a constitutively active kinase, whose activity is primarily determined by the cellular protein level [46], we reasoned that CPX-induced phosphorylation of Cdc25A (S82) is through upregulating protein expression of CK1α

Summary

Introduction

Ciclopirox olamine (CPX), which has a broad spectrum of action against dermatophytes, yeast, filamentous fungi and bacteria [1], has been widely used for the treatment of superficial fungal infection for over 20 years [2]. Recent studies have implicated that CPX has potent anticancer activity, by inhibiting cell proliferation and inducing cell death in tumor cells [3,4,5,6,7,8,9,10,11,12,13,14,15]. A phase I clinical trial study has shown that oral administration of CPX at a dose of 40 mg/m2 once daily for 5 days is well tolerated in patients, and induces disease stabilization and/ or hematologic improvement in 2/3 patients with advanced www.impactjournals.com/Genes&Cancer hematologic malignancies [22]. CPX has emerged as a new and promising anticancer agent

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Conclusion