title: SNX3-dependent regulation of epidermal growth factor receptor (EGFR) trafficking and degradation by aspirin in epidermoid carcinoma (A-431) cells.
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.
authors.affiliation: Laboratory of Membrane Trafficking and Immunoregulation, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore.
authors.forename: Kher Hsin
authors.initials: KH
authors.lastname: Chiow
authors.forename: Yingrou
authors.initials: Y
authors.lastname: Tan
authors.forename: Rong Yuan
authors.initials: RY
authors.lastname: Chua
authors.forename: Dachuan
authors.initials: D
authors.lastname: Huang
authors.forename: Mah Lee Mary
authors.initials: ML
authors.lastname: Ng
authors.forename: Federico
authors.initials: F
authors.lastname: Torta
authors.forename: Markus R
authors.initials: MR
authors.lastname: Wenk
authors.forename: Siew Heng
authors.initials: SH
authors.lastname: Wong
mesh_terms: D001241:Aspirin / Q000494:pharmacology*; D001483:Base Sequence; D001693:Biological Transport, Active / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004705:Endocytosis / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D016253:Microscopy, Immunoelectron; D008954:Models, Biological; D011990:Receptors, Transferrin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058305:Sorting Nexins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D011990:Receptors, Transferrin; C513980:SNX3 protein, human; D058305:Sorting Nexins; D066246:ErbB Receptors; D001241:Aspirin