Lipocalin 2, a new GADD153 target gene, as an apoptosis inducer of endoplasmic reticulum stress in lung cancer cells

• Published in: Toxicology and applied pharmacology 2012-09, Vol.263 (3), p.330-337
• Main Authors: Hsin, I-Lun, Hsiao, Yueh-Chieh, Wu, Ming-Fang, Jan, Ming-Shiou, Tang, Sheau-Chung, Lin, Yu-Wen, Hsu, Chung-Ping, Ko, Jiunn-Liang
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Acute-Phase Proteins - metabolism; APOPTOSIS; Apoptosis - drug effects; Biological and medical sciences; CALCIUM; Cell Line, Tumor; CHROMATIN; Chromatin Immunoprecipitation; DNA; DOSES; ENDOPLASMIC RETICULUM; Endoplasmic Reticulum Stress - drug effects; ER stress; GADD153/CHOP; Gene Silencing; GENES; Humans; Lipocalin 2/NGAL; Lipocalin-2; Lipocalins - metabolism; Lung Neoplasms - pathology; LUNGS; Medical sciences; NEOPLASMS; Pneumology; PROMOTERS; Proto-Oncogene Proteins - metabolism; Thapsigargin; Thapsigargin - pharmacology; TOXICITY; Toxicology; Transcription Factor CHOP - genetics; TRANSCRIPTION FACTORS; Tumors of the respiratory system and mediastinum; Unfolded protein response
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2012.07.005

Endoplasmic reticulum (ER) stress is activated under severe cellular conditions. GADD153, a member of the C/EBP family, is an unfolded protein response (UPR) responsive transcription factor. Increased levels of lipocalin 2, an acute phase protein, have been found in several epithelial cancers. The aim of this study is to investigate the function of lipocalin 2 in lung cancer cells under ER stress. Treatment with thapsigargin, an ER stress activator, led to increases in cytotoxicity, ER stress, apoptosis, and lipocalin 2 expression in A549 cells. GADD153 silencing decreased lipocalin 2 expression in A549 cells. On chromatin immunoprecipitation assay, ER stress increased GADD153 DNA binding to lipocalin 2 promoter. Furthermore, silencing of lipocalin 2 mitigated ER stress-mediated apoptosis in A549 cells. Our findings demonstrated that lipocalin 2 is a new GADD153 target gene that mediates ER stress-induced apoptosis. [Display omitted] ► We demonstrate that Lipocalin 2 is a new GADD153 target gene. ► Lipocalin 2 mediates ER stress-induced apoptosis. ► ER stress-induced lipocalin 2 expression is calcium-independent in A549 cells. ► Lipocalin 2 dose not play a major role in ER stress-induced autophagy.