TY - JOUR
T1 - Increased levels and defective glycosylation of MRPs in ovarian carcinoma cells resistant to oxaliplatin
AU - Beretta, Giovanni Luca
AU - Benedetti, Valentina
AU - Cossa, Giacomo
AU - Assaraf, Yehuda G.A.
AU - Bram, Eran
AU - Gatti, Laura
AU - Corna, Elisabetta
AU - Carenini, Nives
AU - Colangelo, Donato
AU - Howell, Stephen B.
AU - Zunino, Franco
AU - Perego, Paola
N1 - Funding Information:
This work was supported by Associazione Italiana per la Ricerca sul Cancro and Ministero della Salute and by the European Community grant CHEMORES. We thank Mrs. Enrica Favini for technical support.
PY - 2010/4
Y1 - 2010/4
N2 - 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 overexpression 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.
AB - 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 overexpression 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.
KW - ABC transporters
KW - Cellular resistance
KW - MRP4
KW - Ovarian carcinoma
KW - Oxaliplatin
UR - https://www.scopus.com/pages/publications/77249107728
U2 - 10.1016/j.bcp.2009.12.002
DO - 10.1016/j.bcp.2009.12.002
M3 - Article
SN - 0006-2952
VL - 79
SP - 1108
EP - 1117
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 8
ER -