PPM-18, an Analog of Vitamin K, Induces Autophagy and Apoptosis in Bladder Cancer Cells Through ROS and AMPK Signaling Pathways

PPM-18, identified as a novel analog of vitamin K, has been reported to play a critical role in the suppression of seizures. However, the concerns that whether PPM-18, like vitamin K, exerts Anticancer activity remain to be further investigated. Here, we found that PPM-18 remarkably suppressed the proliferation and induced Apoptosis in bladder Cancer cells. Furthermore, a significant autophagic effect of PPM-18 on bladder Cancer cells was also demonstrated, which profoundly promoted apoptotic cell death. Mechanistically, PPM-18 activated AMP-activated protein kinase (AMPK), whereas it repressed PI3K/Akt and mTORC1 pathways in bladder Cancer cells. Inhibition of AMPK markedly relieved PPM-18-induced Autophagy and Apoptosis, indicating that PPM-18 is able to induce Autophagy and Apoptosis in bladder Cancer cells via AMPK activation. Moreover, Reactive Oxygen Species (ROS) were notably accumulated in PPM-18-treated bladder Cancer cells, and treatment with ROS scavengers not only eliminated ROS production but also abrogated AMPK activation, which eventually rescued bladder Cancer cells from PPM-18-triggered Autophagy and apoptotic cell death. In bladder Cancer xenografts, the Anticancer activities of PPM-18, including suppressing the growth of tumors and inducing Autophagy and Apoptosis in tumor cells, were also established. Collectively, this study was the first to demonstrate the Anticancer effect of PPM-18 on bladder Cancer cells in vitro and in vivo through eliciting Autophagy and Apoptosis via ROS and AMPK pathways, which might provide new insights into the potential utilization of PPM-18 for future bladder Cancer treatment.