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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.00968

PINK1/Parkin-mediated mitophagy regulation by ROS alleviates Rocaglamide A-induced apoptosis in pancreatic cancer cells

 Chun Le Zhao1, Ruizhi He1, Ming Shen1, Feng Zhu1, Yuhui Liu1, Hua Chen1, Min Wang1, Xu Li1* and Renyi Qin1
  • 1Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China

Pancreatic cancer (PC) is a highly lethal disease and effective treatment of PC patients remains an enormous challenge. Rocaglamide A (Roc-A), a bioactive molecule isolated from the medicinal plant Aglaia elliptifolia, has attracted considerable attention as a therapeutic option for numerous cancer treatments. However, the effects and underlying mechanism of action of Roc-A in PC is still poorly understood. Here we found that Roc-A inhibited growth and stimulated apoptosis by induction of mitochondria dysfunction in PC cells in vitro and in vivo. Moreover, Roc-A accelerated autophagosome synthesis and triggered mitophagy involving the PINK1/Parkin signal pathway. We also demonstrated that inhibition of autophagy/mitophagy can sensitize PC cells to Roc-A. Finally, Roc-A treatment results in a significant accumulation of intracellular reactive oxygen species (ROS) and pretreatment of cells with the ROS scavenger N-acetylcysteine reversed the apoptosis and autophagy/mitophagy induced by Roc-A. Together, our results provide novel insights into the mechanism of action of Roc-A. Our findings indicate Roc-A as a potential therapeutic agent against PC and suggest that the combination inhibition of autophagy and mitophagy may be a potential therapeutic strategy in PC.

Keywords: Rocaglamide A, mitophagy, Apoptosis, ROS, Pancreatic Cancer

Received: 13 Apr 2019; Accepted: 29 Jul 2019.

Copyright: © 2019 Zhao, He, Shen, Zhu, Liu, Chen, Wang, Li and Qin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Xu Li, Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China, 2013tj0574@hust.edu.cn