Down-regulation of epidermal growth factor receptor by curcumin-induced UBE1L in human bronchial epithelial cells |
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| Institution: | 1. Department of Nutrition and Food Safety, Key Laboratory of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China;2. Department of Cardiothoracic Surgery, Nanjing First Hospital, Nanjing Medical University Affiliated Hospital, Nanjing, Jiangsu 210001, China;1. Laboratory of Molecular Cell Biology, Department of Zoology, Faculty of Science, Assiut University, Assiut 71516, Egypt;2. Department of Biology, Faculty of Science, King Khalid University, Abha, Saudi Arabia;3. Laboratory of Molecular Membrane Biology, Nencki Institute of Experimental Biology, 3 Pasteur St., 02-093 Warsaw, Poland;1. Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA;2. Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA;1. Center of Rheumatology Research, Landspitali – The University Hospital of Iceland, Reykjavik, Iceland;2. Department of Immunology, Landspitali – The University Hospital of Iceland, Reykjavik, Iceland;3. Department of Biochemistry and Molecular Biology, Faculty of Medicine, Biomedical Center, University of Iceland, 101 Reykjavik, Iceland;4. Department of Immunology, Faculty of Medicine, Biomedical Center, University of Iceland, 101 Reykjavik, Iceland |
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| Abstract: | 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. |
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