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

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

  • Front Pharmacol. 2021 Jul 9;12:684915. doi: 10.3389/fphar.2021.684915.
Huiai Lu 1 2 Chunlei Mei 3 Luhao Yang 3 Junyan Zheng 3 Junwei Tong 3 Fengsen Duan 1 Huageng Liang 4 Ling Hong 1
Affiliations

Affiliations

  • 1 Department of Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
  • 2 National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 4 Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Abstract

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.

Keywords

AMP-activated protein kinase; PPM-18; apoptosis; autophagy; bladder cancer; reactive oxygen species.

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