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

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 i...

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Published in:	Free radical biology & medicine Vol. 131; pp. 225 - 236
Main Authors:	Chen, Xuemei, Hu, Yuan, Zhang, Wenlu, Chen, Ke, Hu, Jie, Li, Xiaosong, Liang, Li, Cai, Xuefei, Hu, Jieli, Wang, Kai, Huang, Ailong, Tang, Ni
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01.02.2019
Subjects:	Acetylcysteine - pharmacology Adenine - analogs & derivatives Adenine - pharmacology Animals Antineoplastic Agents - pharmacology Autophagy Autophagy - drug effects Autophagy - genetics Autophagy-Related Protein 5 - antagonists & inhibitors Autophagy-Related Protein 5 - genetics Autophagy-Related Protein 5 - metabolism Chloroquine - pharmacology Cisplatin Cisplatin - pharmacology Gene Expression Regulation Genes, Reporter Hep G2 Cells Hepatitis B virus - drug effects Hepatitis B virus - genetics Hepatitis B virus - growth & development Hepatitis B virus - metabolism Hepatitis B virus reactivation Hepatitis B virus replication Hepatitis B, Chronic - genetics Hepatitis B, Chronic - metabolism Hepatitis B, Chronic - virology Humans Luminescent Proteins - genetics Luminescent Proteins - metabolism Male Mice Mice, Inbred C57BL Mice, Transgenic Microtubule-Associated Proteins - genetics Microtubule-Associated Proteins - metabolism Proto-Oncogene Proteins c-akt - genetics Proto-Oncogene Proteins c-akt - metabolism Red Fluorescent Protein RNA, Small Interfering - genetics RNA, Small Interfering - metabolism ROS/JNK signaling pathway Sequestosome-1 Protein - genetics Sequestosome-1 Protein - metabolism Signal Transduction TOR Serine-Threonine Kinases - genetics TOR Serine-Threonine Kinases - metabolism Virus Activation - drug effects Virus Replication - drug effects Hepatitis B virus replication ALT MDA Autophagy CQ Cisplatin NAC LC3II pgRNA ROS 3-MA Hepatitis B virus reactivation HBV RFP SQSTM1 ROS/JNK signaling pathway
ISSN:	0891-5849, 1873-4596, 1873-4596
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Summary:	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. [Display omitted] •Cisplatin stimulates HBV replication in vitro and in vivo.•Cisplatin induces autophagy to enhance hepatitis B virus replication.•Inhibition of autophagy or ROS/JNK axis rendered cisplatin-induced HBV biosynthesis.•Cisplatin promotes HBV replication and autophagy by ROS/JNK and AKT/mTOR pathway.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0891-5849 1873-4596 1873-4596
DOI:	10.1016/j.freeradbiomed.2018.12.008