UPF1 increases amino acid levels and promotes cell proliferation in lung adenocarcinoma via the eIF2α-ATF4 axis.

Lei Fang; Huan QI; Peng Wang; Shiqing Wang; Tianjiao LI; Tian Xia; Hailong Piao; Chundong GU

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UPF1 increases amino acid levels and promotes cell proliferation in lung adenocarcinoma via the eIF2α-ATF4 axis.

Author: Lei FANG ¹ ; Huan QI ² ; Peng WANG ¹ ; Shiqing WANG ¹ ; Tianjiao LI ¹ ; Tian XIA ² ; Hailong PIAO ³ ; Chundong GU ⁴
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1. Department of Thoracic Surgery, Lung Cancer Diagnosis and Treatment Center of Dalian, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
2. CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
3. CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China. guchundong@dmu.edu.cn, hpiao@dicp.ac.cn.
4. Department of Thoracic Surgery, Lung Cancer Diagnosis and Treatment Center of Dalian, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China. guchundong@dmu.edu.cn.
Publication Type:Journal Article
Keywords: Activating transcription factor 4 (ATF4); Amino acid metabolism; Lung adenocarcinoma; Up-frameshift 1 (UPF1)
MeSH: Activating Transcription Factor 4/genetics*; Adenocarcinoma of Lung; Amino Acids; Cell Proliferation; Eukaryotic Initiation Factor-2; Humans; Lung Neoplasms; RNA Helicases/metabolism*; RNA, Messenger/metabolism*; Trans-Activators/metabolism*
From: Journal of Zhejiang University. Science. B 2022;23(10):863-875
CountryChina
Language:English
Abstract: Up-frameshift 1 (UPF1), as the most critical factor in nonsense-mediated messenger RNA (mRNA) decay (NMD), regulates tumor-associated molecular pathways in many cancers. However, the role of UPF1 in lung adenocarcinoma (LUAD) amino acid metabolism remains largely unknown. In this study, we found that UPF1 was significantly correlated with a portion of amino acid metabolic pathways in LUAD by integrating bioinformatics and metabolomics. We further confirmed that UPF1 knockdown inhibited activating transcription factor 4 (ATF4) and Ser51 phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), the core proteins in amino acid metabolism reprogramming. In addition, UPF1 promotes cell proliferation by increasing the amino-acid levels of LUAD cells, which depends on the function of ATF4. Clinically, UPF1 mRNA expression is abnormal in LUAD tissues, and higher expression of UPF1 and ATF4 was significantly correlated with poor overall survival (OS) in LUAD patients. Our findings reveal that UPF1 is a potential regulator of tumor-associated amino acid metabolism and may be a therapeutic target for LUAD.