SNX3-dependent regulation of epidermal growth factor receptor (EGFR) trafficking and degradation by aspirin in epidermoid carcinoma (A-431) cells |
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Authors: | Kher?Hsin?Chiow Yingrou?Tan Rong?Yuan?Chua Dachuan?Huang Mah?Lee?Mary?Ng Federico?Torta Markus?R?Wenk Email author" target="_blank">Siew?Heng?WongEmail author |
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Institution: | (1) Immunology Programme, Laboratory of Membrane Trafficking and Immunoregulation, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Republic of Singapore;(2) Laboratory of Flavivirus, National University of Singapore, Singapore, Republic of Singapore;(3) Department of Microbiology, National University of Singapore, Singapore, Republic of Singapore;(4) Department of Biochemistry, National University of Singapore, Singapore, Republic of Singapore;(5) Department of Biological Sciences, National University of Singapore, Singapore, Republic of Singapore;(6) Mechanobiology Institute, National University of Singapore, Singapore, Republic of Singapore; |
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Abstract: | Since being introduced globally as aspirin in 1899, acetylsalicylic acid has been widely used as an analgesic, anti-inflammation,
anti-pyretic, and anti-thrombotic drug for years. Aspirin had been reported to down-regulate surface expression of CD40, CD80,
CD86, and MHCII in myeloid dendritic cells (DC), which played essential roles in regulating the immune system. We hypothesized
that the down-regulation of these surface membrane proteins is partly due to the ability of aspirin in regulating trafficking/sorting
of endocytosed surface membrane proteins. By using an established epidermoid carcinoma cell line (A-431), which overexpresses
the epidermal growth factor receptor (EGFR) and transferrin receptor (TfnR), we show that aspirin (1) reduces cell surface
expression of EGFR and (2) accumulates endocytosed-EGFR and -TfnR in the early/sorting endosome (ESE). Further elucidation
of the mechanism suggests that aspirin enhances recruitment of SNX3 and SNX5 to membranes and consistently, both SNX3 and
SNX5 play essential roles in the aspirin-mediated accumulation of endocytosed-TfnR at the ESE. This study sheds light on how
aspirin may down-regulate surface expression of EGFR by inhibiting/delaying the exit of endocytosed-EGFR from the ESE and
recycling of endocytosed-EGFR back to the cell surface. |
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