The Copper Export Pump ATP7B Modulates the Cellular Pharmacology of Carboplatin in Ovarian Carcinoma Cells

Abstract

Human tumor cells lines with acquired resistance to cisplatin (DDP) and carboplatin (CBDCA) are often cross-resistant to copper and vice versa, and some DDP-resistant cells overexpress the copper export pump ATP7B. We sought to demonstrate that ATP7B directly mediates resistance to DDP and CBDCA by stably transfecting human carcinoma cells with a vector designed to express ATP7B.

Confocal Microscopic Analysis of the Interaction between Cisplatin and the Copper Transporter ATP7B in Human Ovarian Carcinoma Cells

“…The subcellular localization of ECFP-ATP7B also corresponded to the distribution of endogenous ATP7B under non-Cu-exposed conditions as reported by other investigators (30). The ECFP-ATP7B fusion protein appeared to be functional in that it conferred a degree of resistance to Cu and DDP that was actually higher, 1.9-and 4.1-fold, respectively, than that produced by expression of the native protein from the same type of vector, which was 1.2-and 2.6-fold, respectively (37). The ECFP-ATP7B fusion protein also reduced both the basal level of cellular Cu (data not shown) and the accumulation of Cu and DDP.…”

“…The enrichment assays offer particularly cogent evidence of the significance of the degree of resistance conferred by ATP7B because both sensitive and resistant cells are exposed to exactly the same culture conditions throughout the assay (38). It is of interest that in all of the assay and cell systems studied thus far, ATP7B appears to render cells more resistant to DDP than to Cu (18,37); the reason for this remains unknown.…”

Reduced expression of small GTPases and hypermethylation of the folate binding protein gene in cisplatin-resistant cells

“…Recent data from Howell's lab demonstrated that two P-type of ATPases ATP7A and ATP7B are involved in cisplatin resistance in human ovarian carcinoma cells by modulating cellular pharmacology of cisplatin and other metals, suggesting that a sequestration and secretory system may exist (Katano et al, 2002(Katano et al, , 2003. Therefore, it is possible that there might be at least two pathways for the reduced accumulation of cisplatin and other related chemicals in CP-r cells: impaired uptake and active secretion.…”

Abnormal lysosomal trafficking and enhanced exosomal export of cisplatin in drug-resistant human ovarian carcinoma cells

“…Studies of the cellular pharmacology of CDDP in cells overexpressing ATP7A and ATP7B indicate that CDDP is sequestered into vesicles belonging to the secretory pathway as well as lysosomes (7,8). Microscopic analyses with a fluoresceinconjugated CDDP have confirmed that CDDP accumulates in vesicles that contain ATP7A or ATP7B (9,10).…”