机构：[1]Department of Otolaryngology-Head and Neck Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China[2]Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia, United States of America[3]Department of Otolaryngology, Traditional Chinese Medicine Hospital of Guangdong Province, Guangzhou, China大德路总院珠海院区耳鼻喉科耳鼻喉科广东省中医院[4]Department of Biosynthesis, School of Pharmacy, Fudan University, Shanghai, China
Nedaplatin, a cisplatin analog, was developed to reduce the toxicity of cisplatin, whereas it can be cross-resistant with cisplatin in some circumstances. This study aimed to investigate the role of autophagy in nedaplatin induced cell death in cisplatin-resistant nasopharyngeal carcinoma cells. Here, we showed that HNE1/DDP and CNE2/DDP cells were resistant to nedaplatin-induced cell death with reduced apoptotic activity. Nedaplatin treatment resulted in autophagosome accumulation and increased expression of LC3-II, indicating the induction of autophagy by nedaplatin in HNE1/DDP and CNE2/DDP cells. Inhibition of autophagy by Bafilomycin A1 (Baf A1) and 3-Methyladenine (3-MA) remarkably enhanced the antitumor efficacy of nedaplatin in HNE1/DDP and CNE2/DDP cells, suggesting that the resistance to nedaplatin-induced cell death was caused by enhanced autophagy in nedaplatin-resistant NPC cells. Additionally, Baf A1 enhanced reactive oxygen species (ROS) generation and apoptosis induced by nedaplatin in HNE1/DDP cells. Mechanistically, nedaplatin treatment caused activation of ERK1/2 and suppression of Akt/mTOR signaling pathways. While inhibition of ERK1/2 by MEK1/2 inhibitor, U0126, could reduce the expression of LC3-II in nedaplatin-resistant NPC cells. Furthermore, suppression of ROS could inhibit nedaplatin-induced ERK activation in HNE1/DDP cells, indicating that ROS and ERK were involved in nedaplatin-induced autophagy. Together, these findings suggested that autophagy played a cytoprotective role in nedaplatin-induced cytotoxicity of HNE1/DDP and CNE2/DDP cells. Furthermore, our results highlighted a potential approach to restore the sensitivity of cisplatin-resistant nasopharyngeal cancer cells to nedaplatin in combination with autophagy inhibitors.
基金：
National Key Basic Research Program of ChinaNational Basic Research Program of China [2015CB931800]; Shanghai Science and Technology CommissionScience & Technology Commission of Shanghai Municipality (STCSM)Shanghai Science & Technology Committee [13431900303]; Shanghai Health and Family Planning Commission [2013012]
第一作者机构：[1]Department of Otolaryngology-Head and Neck Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
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推荐引用方式(GB/T 7714)：
Liu Zhongyu,Liu Jun,Li Li,et al.Inhibition of Autophagy Potentiated the Antitumor Effect of Nedaplatin in Cisplatin-Resistant Nasopharyngeal Carcinoma Cells[J].PLOS ONE.2015,10(8):doi:10.1371/journal.pone.0135236.
APA：
Liu, Zhongyu,Liu, Jun,Li, Li,Nie, Dan,Tao, Qilei...&Ju, Dianwen.(2015).Inhibition of Autophagy Potentiated the Antitumor Effect of Nedaplatin in Cisplatin-Resistant Nasopharyngeal Carcinoma Cells.PLOS ONE,10,(8)
MLA：
Liu, Zhongyu,et al."Inhibition of Autophagy Potentiated the Antitumor Effect of Nedaplatin in Cisplatin-Resistant Nasopharyngeal Carcinoma Cells".PLOS ONE 10..8(2015)
