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

摘要

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 Asn 15 , 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.