Ciclopirox induces autophagy through reactive oxygen species-mediated activation of JNK signaling pathway

Abstract

Ciclopirox olamine (CPX), a fungicide, has been demonstrated as a potential anticancer agent. However, the underlying anticancer mechanism is not well understood. Here, we found that CPX induced autophagy in human rhabdomyosarcoma (Rh30 and RD) cells. It appeared that CPX-induced autophagy was attributed to induction of reactive oxygen species (ROS), as N-acetyl-L-cysteine (NAC), a ROS scavenger and antioxidant, prevented this process. Furthermore, we observed that CPX induced activation of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 MAPK, which was also blocked by NAC. However, only inhibition of JNK (with SP600125) or expression of dominant negative c-Jun partially prevented CPX-induced autophagy, indicating that ROS-mediated activation of JNK signaling pathway contributed to CPX-induced autophagy. Of interest, inhibition of autophagy by chloroquine (CQ) enhanced CPX-induced cell death, indicating that CPX-induced autophagy plays a pro-survival role in human rhabdomyosarcoma cells. Our finding suggests that the combination with autophagy inhibitors may be a novel strategy in potentiating the anticancer activity of CPX for treatment of rhabdomyosarcoma.

β-Elemene induces apoptosis of human rheumatoid arthritis fibroblast-like synoviocytes via reactive oxygen species-dependent activation of p38 mitogen-activated protein kinase

“…In agreement with our findings, a previous 271 study has shown that activation of p38 MAPK contributes to the 272 anti-proliferation effect of b-elemene in glioblastoma cells [15]. 273 Substantial ROS has been found to activate MAPK signaling 274 cascades [28]. Consistent with activation of p38 MAPK, we found 275 that b-elemene treatment caused a significant increase in the 276 production of ROS.…”

Reactive Oxygen Species-Mediated c-Jun NH 2 -Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction

“…The reason for this discrepancy is unclear, but it may be due to the different cell lines or experimental conditions used. Recent evidence highlights the role of ROS in JNK-activated autophagosome formation (46,47), and ROS has also been reported to be closely associated with HBx-and HBV-mediated biological processes (50,51,61). We therefore further investigated the role of ROS in HBx-activated JNK signaling and autophagosome formation.…”

“…Recent work has revealed that ROS may play an important role in JNK-dependent autophagy regulation (46)(47)(48)(49), while HBx treatment has been reported to cause ROS generation in hepatoma cells (50,51). We thus investigated the role of ROS in HBx-induced JNK activation and the ensuing autophagosome formation.…”

The Protective Role of Autophagy in Human Vocal Fold Fibroblasts under Cigarette Smoke Extract Exposure: A New Insight into the Study of Reinke's Edema

“…CS is a potent source of ROS generation [8,9]. The involvement of ROS in the induction of autophagy has been proven in many studies, as the ROS scavenger and antioxidant can prevent the formation of autophagosomes and the degradation of proteins [10,11,12,13]. …”