Core fucosylation of copper transporter 1 plays a crucial role in cisplatin-resistance of epithelial ovarian cancer by regulating drug uptake.

Abstract

Core fucosylation catalyzed by core fucosyltransferase (Fut8) contributes to the progressions of epithelial ovarian cancer (EOC). Copper transporter 1 (CTR1), which contains one N-glycan on Asn15 , mediates cellular transport of cisplatin (cDDP), and plays an important role in the process of cDDP-resistance in EOC. In the present study, we found that the core fucosylation level elevated significantly in the sera of cDDP-treated EOC patients. The in vitro assays also indicate that core fucosylation of CTR1 was significantly upregulated in cDDP-resistant A2780CP cells compared to the cDDP-sensitive A2780S cells. Intriguingly, the hyper core fucosylation suppressed the CTR1-cDDP interactions and cDDP-uptake into A2780CP cells. Conversely, contrast to the Fut8+/+ mouse ovarian epithelial cells, the Fut8-deleted (Fut8-/- ) cells obviously showed higher cDDP-uptake. Furthermore, the recovered core fucosylation induced the suppression of cDDP-uptake in Fut8-restored ovarian epithelial cells. In addition, the core fucosylation could regulate the phosphorylation of cDDP-resistance-associated molecules, such as AKT, ERK, JNK, and mTOR. Our findings suggest that the core fucosylation of CTR1 plays an important role in the cellular cDDP-uptake and thus provide new strategies for improving the outcome of cDDP based chemotherapy of EOC.