Ciclopirox drives growth arrest and autophagic cell death through STAT3 in gastric cancer cells
Lingyan Chen, Dejian Chen, Jiwei Li, Lipeng He, Ting Chen, Dandan Song, Shuang Shan, Jiaxin Wang, Xiaoang Lu, Bin Lü
Abstract
Ciclopirox (CPX), an antifungal drug, has recently been identified as a promising agent for cancer treatment. However, the effects and underlying mechanism of CPX as an antitumor agent of gastric cancer (GC) remain largely unknown. Here, we found that CPX dramatically suppresses GC xenograft growth in vitro via inhibiting proliferation and stimulating autophagic cell death rather than apoptosis. Moreover, CPX (20 mg/kg, intraperitoneally) substantially inhibits GC xenograft tumor growth in vivo. Mechanistically, CPX promotes growth arrest and autophagic cell death through suppressing the phosphorylation of signal transducers and activators of transcription 3 (STAT3) at tyrosine 705 (Tyr705) and serine 727 (Ser727) sites, respectively. Additionally, CPX induces STAT3 ubiquitination, which subsequently leads to a decrease in the p-STAT3 (Ser727) level. On the other hand, CPX represses the p-STAT3 (Tyr705) level via p-Src (Tyr416) inhibition. Collectively, our findings unmask a novel mechanism by which CPX regulates growth and autophagic cell death in GC cells via regulating the phosphorylation of STAT3 both at Tyr705 and Ser727 residues, and suggest that CPX may be a potential treatment for GC.