Increased levels and defective glycosylation of MRPs in ovarian carcinoma cells resistant to oxaliplatin

Giovanni Luca Beretta , Valentina Benedetti , Giacomo Cossa , Yehuda G.A. Assaraf , Eran Bram , Laura Gatti , Elisabetta Corna , Nives Carenini , Donato Colangelo , Stephen B. Howell , Franco Zunino , Paola Perego

Pt compounds still represent the mainstay of the treatment of ovarian carcinoma. The aim of the present study was to investigate the molecular bases of resistance to Pt drugs using an oxaliplatin-resistant ovarian carcinoma cell model IGROV-1/OHP. These cells exhibited high levels of resistance to oxaliplatin, cross-resistance to cisplatin and topotecan and displayed a marked accumulation defect of Pt drugs. This feature was associated with increased expression and altered N-linked glycosylation of ATP binding cassette transporters MRP1 and MRP4. Pre-treatment with tunicamycin, which inhibits the biosynthesis of N-linked oligosaccharides, decreased the accumulation of Pt in sensitive cells exposed to oxaliplatin or cisplatin and increased the electrophoretic mobility of MRP1 and MRP4, reproducing the association between decreased glycosylation of MRP1 and MRP4 and decreased Pt accumulation observed in the resistant IGROV-1/OHP cells. The observed N-glycosylation defect of oxaliplatin-resistant cells was linked to reduced levels of N-acetylglucosamine-1-phosphotransferase (GNPTG) and mannosyl (alpha-1,6-)-glycoprotein beta-1,6-N-acetyl-glucosaminyltransferase (MGAT5). This feature, observed in IGROV-1/OHP cells, was associated with decreased retention of Pt drugs. In addition, the over-expression of fully glycosylated MRP1 or MRP4 in tumor cell line of ovarian origin was associated with resistance to oxaliplatin and cisplatin. Our findings, showing that development of resistance to oxaliplatin results in up-regulation of MRPs, support that patients with oxaliplatin-refractory ovarian carcinomas may benefit from non-Pt based regimens which do not contain MRP1 and MRP4 substrates.

Mots clés: Oxaliplatin; Ovarian carcinoma; ABC transporters; Cellular resistance; MRP4

Giovanni Luca Beretta, Valentina Benedetti, Giacomo Cossa, Yehuda G.A. Assaraf, Eran Bram, et al.. Increased levels and defective glycosylation of MRPs in ovarian carcinoma cells resistant to oxaliplatin. Biochemical Pharmacology, 2010, 79 (8), pp.1108. ⟨10.1016/j.bcp.2009.12.002⟩. ⟨hal-00565098⟩