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.
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This study was supported by grants from National Key Basic Research Program of China (2015CB931800 and 2013CB932502), Science and Technology Program of Guangzhou, China (2013 J4500041), National Natural Science Foundation of China (NSFC-Guangdong Joint Fund Project, U1401226), the National Natural Science Foundation of China (81,573,332), Shanghai Science and Technology Funds (14,431,900,200), the 2017 CMA-L’OREAL China Skin/Hair Grant (H2017–004), and Special Research Foundation of State Key Laboratory of Medical Genomics and Collaborative Innovation Center of Systems Biomedicine. The funders had no roles in study design, data collection and analysis, decision to publish, or preparation of manuscript.
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Boyang Zhang and Jiajun Fan contributed equally to this work.
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Zhang, B., Fan, J., Zhang, X. et al. Targeting asparagine and autophagy for pulmonary adenocarcinoma therapy. Appl Microbiol Biotechnol 100, 9145–9161 (2016). https://doi.org/10.1007/s00253-016-7640-3
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DOI: https://doi.org/10.1007/s00253-016-7640-3