2. Academic Validation
  3. Cisplatin induces autophagy to enhance hepatitis B virus replication via activation of ROS/JNK and inhibition of the Akt/mTOR pathway

Cisplatin induces autophagy to enhance hepatitis B virus replication via activation of ROS/JNK and inhibition of the Akt/mTOR pathway

  • Free Radic Biol Med. 2019 Feb 1;131:225-236. doi: 10.1016/j.freeradbiomed.2018.12.008.
Xuemei Chen 1,  Yuan Hu 1,  Wenlu Zhang 1,  Ke Chen 1,  Jie Hu 1,  Xiaosong Li 2,  Li Liang 1,  Xuefei Cai 1,  Jieli Hu 1,  Kai Wang 3,  Ailong Huang 4,  Ni Tang 5
Affiliations

Affiliations

  • 1 Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
  • 2 The First Affiliated Hospital, Chongqing Medical University, Chongqing, China.
  • 3 Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. Electronic address: wangkai@cqmu.edu.cn.
  • 4 Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. Electronic address: ahuang@cqu.edu.cn.
  • 5 Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. Electronic address: nitang@cqmu.edu.cn.
PMID: 30550853 DOI: 10.1016/j.freeradbiomed.2018.12.008
Abstract

Chronic hepatitis B virus (HBV) Infection remains a serious global health concern. Cisplatin is a chemotherapeutic agent commonly used to treat various cancers. However, HBV-infected patients receiving chemotherapy are at risk of HBV reactivation via unknown mechanisms, which we aimed to elucidate in this study. We found that Autophagy plays a central role in cisplatin-induced HBV replication. Cisplatin treatment induced Autophagy in both HBV-replicating cells and an HBV-transgenic mouse model as evident from marked upregulation of microtubule-associated protein 1 light chain 3 (LC3)-II and the accumulation of red fluorescent protein (RFP)-LC3 puncta. Cisplatin induced complete autophagic flux, which was detected via monitoring of p62 degradation and RFP-GFP-LC3 expression. Inhibition of Autophagy by chloroquine, 3-methyladenine, or Atg5 knockdown significantly attenuated cisplatin-induced HBV replication. Additionally, cisplatin-induced Autophagy could be significantly attenuated by using the ROS scavenger N-acetyl-l-cysteine. Mechanically, cisplatin promoted HBV replication and Autophagy through ROS/JNK and Akt/mTOR signaling. Inhibition of JNK or activation of Akt/mTOR signaling reversed cisplatin-mediated Autophagy and HBV replication promotion. In contrast, suppression of Akt/mTOR signaling further promoted cisplatin-induced HBV replication. Finally, pharmacotherapeutic inhibition of Autophagy or ROS production impaired HBV production induced by cisplatin in vivo. Together, our results indicate that ROS/JNK and mTOR/AKT-mediated Autophagy plays an important role in cisplatin-induced HBV reactivation.

Keywords

Autophagy; Cisplatin; Hepatitis B virus reactivation; Hepatitis B virus replication; ROS/JNK signaling pathway.

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