title: Targeting asparagine and autophagy for pulmonary adenocarcinoma therapy.
abstract: The mounting number of patients with pulmonary adenocarcinoma (ADCA) is subjected to poor prognosis and heavy mortality, which prompts us to explore new potential therapeutics for lung ADCA. Herein, we reported a novel approach for lung ADCA therapy by abolishing autophagy and asparagine. We demonstrated that deprivation of asparagine by asparaginase could induce significant cytotoxicity and apoptosis in A549 and H1975 cells. During this process, autophagy was triggered by the asparaginase treatment, characterized by the autophagic flux with three main stages including formation of autophagosomes, lysosomes fused with autophagosomes, and degradation of autophagosomes by lysosomes. Importantly, suppression of autophagy could notably enhance the cytotoxicity and accelerate the caspase 3-dependent apoptosis induced by asparaginase. Furthermore, suppression of reactive oxygen species (ROS) could attenuated both the cytotoxicity and autophagy induced by asparaginase, while inhibition of autophagy promoted the generation of ROS in A549 and H1975 cells, indicating the essential role of ROS in asparagine deprivation therapy in lung ADCA cells. Our results demonstrated that targeting cytoprotective autophagy and asparagine could potently kill the ADCA cells, which highlighted a novel approach for lung ADCA therapy in the clinics.
authors.affiliation: Research Center for Clinical Pharmacology, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Road, Guangzhou, 510515, China.
authors.forename: Boyang
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Biosynthesis and Key Laboratory of Smart Drug Delivery MOE, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai, 201203, China.
authors.forename: Jiajun
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Biosynthesis and Key Laboratory of Smart Drug Delivery MOE, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai, 201203, China.
authors.forename: Xuyao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Research Center for Clinical Pharmacology, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Road, Guangzhou, 510515, China.
authors.forename: Weitao
authors.initials: W
authors.lastname: Shen
authors.affiliation: Instrumental Analysis Center, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Zhonglian
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Instrumental Analysis Center, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.affiliation: Research Center for Clinical Pharmacology, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Road, Guangzhou, 510515, China. xuzy9806@vip.sina.com.
authors.forename: Zhongyuan
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Biosynthesis and Key Laboratory of Smart Drug Delivery MOE, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai, 201203, China. dianwenju@fudan.edu.cn.
authors.forename: Dianwen
authors.initials: D
authors.lastname: Ju
mesh_terms: D000230:Adenocarcinoma / Q000628:therapy*; D017209:Apoptosis; D001215:Asparaginase / Q000008:administration & dosage*; D001216:Asparagine / Q000037:antagonists & inhibitors*; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival; D006801:Humans; D008175:Lung Neoplasms / Q000628:therapy*; D008954:Models, Biological; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D001216:Asparagine; D001215:Asparaginase
keywords: Apoptosis; Asparaginase; Asparagine deprivation therapy; Autophagy; Reactive oxygen species