title: Decreased levels of baseline and drug-induced tubulin polymerisation are hallmarks of resistance to taxanes in ovarian cancer cells and are associated with epithelial-to-mesenchymal transition.
abstract: BACKGROUND
  ABCB1 expression is uncommon in ovarian cancers in the clinical setting so we investigated non-MDR mechanisms of resistance to taxanes.
  
  
  METHODS
  We established eight taxane-resistant variants from the human ovarian carcinoma cell lines A2780/1A9, ES-2, MES-OV and OVCAR-3 by selection with paclitaxel or docetaxel, with counter-selection by the transport inhibitor valspodar.
  
  
  RESULTS
  Non-MDR taxane resistance was associated with reduced intracellular taxane content compared to parental controls, and cross-resistance to other microtubule stabilising drugs. Collateral sensitivity to depolymerising agents (vinca alkaloids and colchicine) was observed with increased intracellular vinblastine. These variants exhibited marked decreases in basal tubulin polymer and in tubulin polymerisation in response to taxane exposure. TUBB3 content was increased in 6 of the 8 variants. We profiled gene expression of the parental lines and resistant variants, and identified a transcriptomic signature with two highly significant networks built around FN1 and CDKN1A that are associated with cell adhesion, cell-to-cell signalling, and cell cycle regulation. miR-200 family members miR-200b and miR-200c were downregulated in resistant cells, associated with epithelial to mesenchymal transition (EMT), with increased VIM, FN1, MMP2 and/or MMP9.
  
  
  CONCLUSIONS
  These alterations may serve as biomarkers for predicting taxane effectiveness in ovarian cancer and should be considered as therapeutic targets.
authors.affiliation: Department of Medicine (Oncology), Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: George E
authors.initials: GE
authors.lastname: Duran
authors.affiliation: Department of Medicine (Oncology), Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Yan C
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Department of Medicine (Oncology), Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: François
authors.initials: F
authors.lastname: Moisan
authors.affiliation: Department of Medicine (Oncology), Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: E Brian
authors.initials: EB
authors.lastname: Francisco
authors.affiliation: Department of Medicine (Oncology), Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Branimir I
authors.initials: BI
authors.lastname: Sikic
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D015820:Cadherins / Q000235:genetics; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005353:Fibronectins / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use; D058105:Polymerization / Q000187:drug effects; D043823:Taxoids / Q000494:pharmacology / Q000627:therapeutic use; D014404:Tubulin / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014746:Vimentin / Q000235:genetics; D014747:Vinblastine / Q000494:pharmacology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C493956:CDKN1A protein, human; D015820:Cadherins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C067625:FN1 protein, human; D005353:Fibronectins; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; C498585:TUBB3 protein, human; D043823:Taxoids; D014404:Tubulin; D016159:Tumor Suppressor Protein p53; D014746:Vimentin; D000077143:Docetaxel; D014747:Vinblastine; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D017239:Paclitaxel