N-Glycan fucosylation of epidermal growth factor receptor modulates receptor activity and sensitivity to epidermal growth factor receptor tyrosine kinase inhibitor

Kazuko Matsumoto, Hideyuki Yokote, Tokuzo Arao, Mari Maegawa, Kaoru Tanaka, Yoshihiko Fujita, Chikako Shimizu, Toshiaki Hanafusa, Yasuhiro Fujiwara, Kazuto Nishio
Cancer Science 2008, 99 (8): 1611-7
The glycosylation of cell surface proteins is important for cancer biology processes such as cellular proliferation or metastasis. alpha1,6-Fucosyltransferase (FUT8) transfers a fucose residue to n-linked oligosaccharides on glycoproteins. Herein, we study the effect of fucosylation on epidermal growth factor receptor (EGFR) activity and sensitivity to an EGFR-specific tyrosine kinase inhibitor (EGFR-TKI). The increased fucosylation of EGFR significantly promoted EGF-mediated cellular growth, and the decreased fucosylation by stable FUT8 knockdown weakened the growth response in HEK293 cells. The overexpression of FUT8 cells were more sensitive than the control cells to the EGFR-TKI gefitinib, and FUT8 knockdown decreased the sensitivity to gefitinib. Finally, to examine the effects in a human cancer cell line, we constructed stable FUT8 knockdown A549 cells, and found that these cells also decreased EGF-mediated cellular growth and were less sensitive than the control cells to gefitinib. In conclusion, we demonstrated that the modification of EGFR fucosylation affected EGF-mediated cellular growth and sensitivity to gefitinib. Our results provide a novel insight into how the glycosylation status of a receptor may affect the sensitivity of the cell to molecular target agents.

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