Down-regulation of epidermal growth factor receptor by curcumin-induced UBE1L in human bronchial epithelial cells.
UBE1L, ubiquitin-activating enzyme E1-like, is the activating enzyme of ISG15ylation (ISG15, interferon stimulated gene 15). Loss of UBE1L and activation of epidermal growth factor receptor (EGFR) signaling are common events in lung carcinogenesis. Curcumin, a well-studied chemopreventive agent, is known to down-regulate EGFR. The present study demonstrated that curcumin decreased EGFR expression in human bronchial epithelial (HBE) Beas-2B cells and lung cancer A549 cells. For the first time, UBE1L was found to be induced by curcumin in HBE cells. Interestingly, overexpression of UBE1L reduced EGFR at posttranslational level in HBE cells. UBE1L triggered EGFR membrane internalization and promoted complex formation between ISG15 and EGFR. Curcumin decreased EGFR downstream signaling pAKT and nuclear factor κB (NF-κB). Overexpression or knockdown of UBE1L also resulted in down-regulation or up-regulation of phosphoinositide 3-kinase/AKT/NF-κB correspondently. In human samples, there was an inverse relationship between UBE1L and EGFR/AKT/NF-κB in non-small cell lung cancer tissues and adjacent tissues. These results uncover a novel chemopreventive mechanism of curcumin in inducing UBE1L and down-regulating EGFR signaling in HBE cells.
Department of Nutrition and Food Safety, Key Laboratory of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
A-Pei
AP
Jiang
Department of Nutrition and Food Safety, Key Laboratory of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
Dong-Hu
DH
Zhou
Department of Nutrition and Food Safety, Key Laboratory of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
Xu-Lian
XL
Meng
Department of Cardiothoracic Surgery, Nanjing First Hospital, Nanjing Medical University Affiliated Hospital, Nanjing, Jiangsu 210001, China.
Ai-Ping
AP
Zhang
Department of Cardiothoracic Surgery, Nanjing First Hospital, Nanjing Medical University Affiliated Hospital, Nanjing, Jiangsu 210001, China.
Cui
C
Zhang
Department of Nutrition and Food Safety, Key Laboratory of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
Xiao-Ting
XT
Li
Department of Nutrition and Food Safety, Key Laboratory of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China. Electronic address: qingfeng@njmu.edu.cn.
Qing
Q
Feng
D001483:Base Sequence; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D017931:DNA Primers; D015536:Down-Regulation / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D066246:ErbB Receptors
Curcumin; Down-regulation; EGFR; UBE1L