title: Glutathione S-transferase P1 (GSTP1) directly influences platinum drug chemosensitivity in ovarian tumour cell lines.
abstract: BACKGROUND
  Chemotherapy response in ovarian cancer patients is frequently compromised by drug resistance, possibly due to altered drug metabolism. Platinum drugs are metabolised by glutathione S-transferase P1 (GSTP1), which is abundantly, but variably expressed in ovarian tumours. We have created novel ovarian tumour cell line models to investigate the extent to which differential GSTP1 expression influences chemosensitivity.
  
  
  METHODS
  Glutathione S-transferase P1 was stably deleted in A2780 and expression significantly reduced in cisplatin-resistant A2780DPP cells using Mission shRNA constructs, and MTT assays used to compare chemosensitivity to chemotherapy drugs used to treat ovarian cancer. Differentially expressed genes in GSTP1 knockdown cells were identified by Illumina HT-12 expression arrays and qRT-PCR analysis, and altered pathways predicted by MetaCore (GeneGo) analysis. Cell cycle changes were assessed by FACS analysis of PI-labelled cells and invasion and migration compared in quantitative Boyden chamber-based assays.
  
  
  RESULTS
  Glutathione S-transferase P1 knockdown selectively influenced cisplatin and carboplatin chemosensitivity (2.3- and 4.83-fold change in IC50, respectively). Cell cycle progression was unaffected, but cell invasion and migration was significantly reduced. We identified several novel GSTP1 target genes and candidate platinum chemotherapy response biomarkers.
  
  
  CONCLUSIONS
  Glutathione S-transferase P1 has an important role in cisplatin and carboplatin metabolism in ovarian cancer cells. Inter-tumour differences in GSTP1 expression may therefore influence response to platinum-based chemotherapy in ovarian cancer patients.
authors.affiliation: Division of Cancer Research, Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
authors.forename: L
authors.initials: L
authors.lastname: Sawers
authors.affiliation: Dundee Cancer Centre, NHS Tayside, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Ferguson
authors.affiliation: Division of Cancer Research, Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
authors.forename: B R
authors.initials: BR
authors.lastname: Ihrig
authors.affiliation: Division of Cancer Research, Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
authors.forename: H C
authors.initials: HC
authors.lastname: Young
authors.affiliation: Bioinformatics and Biostatistics Service, Cancer Research UK, 44 Lincolns Inn Fields, London WC2A 3PX, London, UK.
authors.forename: P
authors.initials: P
authors.lastname: Chakravarty
authors.affiliation: 1] Division of Cancer Research, Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK [2] Cancer Research UK Molecular Pharmacology Unit, Division of Cancer Research, Medical Research Institute, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
authors.forename: C R
authors.initials: CR
authors.lastname: Wolf
authors.affiliation: Division of Cancer Research, Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
authors.forename: G
authors.initials: G
authors.lastname: Smith
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism* / Q000627:therapeutic use; D016190:Carboplatin / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D051549:Glutathione S-Transferase pi / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D010051:Ovarian Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D016190:Carboplatin; D051549:Glutathione S-Transferase pi; D002945:Cisplatin