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

被引：0
作者：
Longlong Xie
Feng Shi
Yueshuo Li
We Li
Xinfang Yu
Lin Zhao
Min Zhou
Jianmin Hu
Xiangjian Luo
Min Tang
Jia Fan
Jian Zhou
Qiang Gao
Weizhong Wu
Xin Zhang
Weihua Liao
Ann M. Bode
Ya Cao
机构：
[1] Key Laboratory of Carcinogenesis and Invasion,Department of Otolaryngology Head and Neck Surgery
[2] Chinese Ministry of Education,Department of Radiology, Xiangya Hospital
[3] Department of Radiology,The Hormel Institute
[4] Xiangya Hospital,undefined
[5] Central South University,undefined
[6] Cancer Research Institute and School of Basic Medical Science,undefined
[7] Xiangya School of Medicine,undefined
[8] Central South University,undefined
[9] Key Laboratory of Carcinogenesis,undefined
[10] Chinese Ministry of Health,undefined
[11] Molecular Imaging Research Center of Central South University,undefined
[12] Key Laboratory for Carcinogenesis and Cancer Invasion,undefined
[13] Chinese Ministry of Education,undefined
[14] Zhongshan Hospital,undefined
[15] Shanghai Medical School,undefined
[16] Fudan University,undefined
[17] Xiangya Hospital,undefined
[18] Central South University,undefined
[19] Central South University,undefined
[20] University of Minnesota,undefined
[21] Research Center for Technologies of Nucleic Acid-Based Diagnostics and Therapeutics Hunan Province,undefined
[22] National Joint Engineering Research Center for Genetic Diagnostics of Infectious Diseases and Cancer,undefined
来源：
Signal Transduction and Targeted Therapy | / 5卷
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摘要：
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.
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