Resistance to paclitaxel in a cisplatin-resistant ovarian cancer cell line is mediated by P-glycoprotein

• Published in: PloS one Vol. 7; no. 7; p. e40717
• Main Authors: Stordal, Britta, Hamon, Marion, McEneaney, Victoria, Roche, Sandra, Gillet, Jean-Pierre, O'Leary, John J, Gottesman, Michael, Clynes, Martin
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 11.07.2012; Public Library of Science (PLoS)
• Subjects: Accumulation; Adenosine triphosphatase; Analysis; Antineoplastic Agents - pharmacology; Apoptosis; ATP Binding Cassette Transporter, Subfamily B - genetics; ATP Binding Cassette Transporter, Subfamily B - metabolism; Biology; Biomarkers - metabolism; Biotechnology; BRCA1 protein; Breast cancer; Cancer; Cancer therapies; Cation Transport Proteins - metabolism; Cell Line, Tumor; Cellular stress response; Chemistry; Chemoresistance; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Copper; Copper Transporter 1; Cytotoxicity; Drug resistance; Drug Resistance, Neoplasm - genetics; Enzymatic activity; Enzyme activity; Enzymes; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genes; Genes, BRCA1; Genetic aspects; Glutathione; Glutathione - metabolism; Glycoproteins; Hematology; Histopathology; Humans; Laboratories; Medical prognosis; Medical research; Medicine; Metabolic Networks and Pathways; Ovarian cancer; Ovarian carcinoma; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; P-Glycoprotein; Paclitaxel; Paclitaxel - pharmacology; Patients; Phenotypes; Platinum; Position (location); Potassium; Protein expression; Proteins; Sodium; Substrates; Systematic review; Taxane; Taxanes; Transporter; United Kingdom > UK; United States > US; Maryland; Ireland
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0040717

The IGROVCDDP cisplatin-resistant ovarian cancer cell line is also resistant to paclitaxel and models the resistance phenotype of relapsed ovarian cancer patients after first-line platinum/taxane chemotherapy. A TaqMan low-density array (TLDA) was used to characterise the expression of 380 genes associated with chemotherapy resistance in IGROVCDDP cells. Paclitaxel resistance in IGROVCDDP is mediated by gene and protein overexpression of P-glycoprotein and the protein is functionally active. Cisplatin resistance was not reversed by elacridar, confirming that cisplatin is not a P-glycoprotein substrate. Cisplatin resistance in IGROVCDDP is multifactorial and is mediated in part by the glutathione pathway and decreased accumulation of drug. Total cellular glutathione was not increased. However, the enzyme activity of GSR and GGT1 were up-regulated. The cellular localisation of copper transporter CTR1 changed from membrane associated in IGROV-1 to cytoplasmic in IGROVCDDP. This may mediate the previously reported accumulation defect. There was decreased expression of the sodium potassium pump (ATP1A), MRP1 and FBP which all have been previously associated with platinum accumulation defects in platinum-resistant cell lines. Cellular localisation of MRP1 was also altered in IGROVCDDP shifting basolaterally, compared to IGROV-1. BRCA1 was also up-regulated at the gene and protein level. The overexpression of P-glycoprotein in a resistant model developed with cisplatin is unusual. This demonstrates that P-glycoprotein can be up-regulated as a generalised stress response rather than as a specific response to a substrate. Mechanisms characterised in IGROVCDDP cells may be applicable to relapsed ovarian cancer patients treated with frontline platinum/taxane chemotherapy.