Drp1-dependent remodeling of mitochondrial morphology triggered by EBV-LMP1 increases cisplatin resistance

• Published in: Signal transduction and targeted therapy 2020-05, Vol.5 (1), p.56, Article 56
• Main Authors: Xie, Longlong, Shi, Feng, Li, Yueshuo, Li, We, Yu, Xinfang, Zhao, Lin, Zhou, Min, Hu, Jianmin, Luo, Xiangjian, Tang, Min, Fan, Jia, Zhou, Jian, Gao, Qiang, Wu, Weizhong, Zhang, Xin, Liao, Weihua, Bode, Ann M., Cao, Ya
• Format: Article
• Language: English
• Subjects: 631/67/1059/153; 631/67/1536; 631/67/327; Animals; Cancer Research; Carcinogenesis; Cell Biology; Cell death; Cell Line, Tumor; Cell survival; Chemoresistance; Chemotherapy; Cisplatin; Cyclin B1; Disease resistance; Dynamin; Dynamins - genetics; Dynamins - metabolism; Epstein-Barr virus; Epstein-Barr Virus Infections - genetics; Epstein-Barr Virus Infections - metabolism; Epstein-Barr Virus Infections - pathology; Female; Herpesvirus 4, Human - genetics; Herpesvirus 4, Human - metabolism; Internal Medicine; Latency; Latent membrane protein 1; Male; Medical prognosis; Medicine; Medicine & Public Health; Membrane proteins; Mice; Mice, Inbred BALB C; Mice, Nude; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial Dynamics; Morphology; Nasopharyngeal carcinoma; Nasopharyngeal Carcinoma - genetics; Nasopharyngeal Carcinoma - metabolism; Nasopharyngeal Carcinoma - pathology; Nasopharyngeal Carcinoma - virology; Nasopharyngeal Neoplasms - genetics; Nasopharyngeal Neoplasms - metabolism; Nasopharyngeal Neoplasms - pathology; Nasopharyngeal Neoplasms - virology; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Oncology; Pathology; Phosphorylation; Proteins; Serine; Throat cancer; Tumorigenesis; Viral Matrix Proteins - genetics; Viral Matrix Proteins - metabolism
• ISSN: 2059-3635; 2095-9907; 2059-3635
• DOI: 10.1038/s41392-020-0151-9

Latent membrane protein 1 (LMP1) is a major Epstein–Barr virus (EBV)-encoded oncoprotein involved in latency infection that regulates mitochondrial functions to facilitate cell survival. Recently, mitochondrial fission has been demonstrated as a crucial mechanism in oncovirus-mediated carcinogenesis. Mitochondrial dynamin-related protein 1 (Drp1)-mediated mitochondrial fission has an impact on the chemoresistance of cancers. However, the mechanism by which oncogenic stress promotes mitochondrial fission, potentially contributing to tumorigenesis, is not entirely understood. The role of Drp1 in the oncogenesis and prognosis of EBV-LMP1-positive nasopharyngeal carcinoma (NPC) was determined in our study. We show that EBV-LMP1 exhibits a new function in remodeling mitochondrial morphology by activating Drp1. A high level of p-Drp1 (Ser616) or a low level of p-Drp1 (Ser637) correlates with poor overall survival and disease-free survival. Furthermore, the protein level of p-Drp1 (Ser616) is related to the clinical stage (TNM stage) of NPC. Targeting Drp1 impairs mitochondrial function and induces cell death in LMP1-positive NPC cells. In addition, EBV-LMP1 regulates Drp1 through two oncogenic signaling axes, AMPK and cyclin B1/Cdk1, which promote cell survival and cisplatin resistance in NPC. Our findings provide novel insight into the role of EBV-LMP1-driven mitochondrial fission in regulating Drp1 phosphorylation at serine 616 and serine 637. Disruption of Drp1 could be a promising therapeutic strategy for LMP1-positive NPC.