ROS generation attenuates the anti-cancer effect of CPX on cervical cancer cells by inducing autophagy and inhibiting glycophagy

Cervical cancer is one of the most common gynecological malignancies with poor prognosis due to constant chemoresistance and repeated relapse. Ciclopirox olamine (CPX), a synthetic antifungal agent, has recently been identified to be a promising anti-cancer candidate. However, the detailed mechanisms related to its anti-cancer effects remain unclear and need to be further elucidated. In this study, we found that CPX could induce proliferation inhibition in cervical cancer cells by targeting PARK7. Further results demonstrated that CPX could induce cytoprotective autophagy by downregulating the expression of PARK7 to activate PRKAA1 or by PARK7-independent accumulation of ROS to inhibit mTOR signaling. Meanwhile, CPX treatment increased the glycogen clustering and glycophagy in cervical cancer cells. The presence of N-acetyl-l-cysteine (NAC), a ROS scavenger, led to further clustering of glycogen in cells by reducing autophagy and enhancing glycophagy, which promoted CPX-induced inhibition of cervical cancer cell proliferation. Together, our study provides new insights into the molecular mechanisms of CPX in the anti-cancer therapy and opens new avenues for the glycophagy in cancer therapeutics. [Display omitted] •CPX induces cytoprotective autophagy and inhibits proliferation of cervical cancer cells by targeting PARK7.•ROS generation attenuates the anticancer effect of CPX by inducing cytoprotective autophagy and inhibiting glycophagy.•ROS-triggered glycogen clustering and inactivation of YAP1 are involved in the anti-cancer effects of CPX.