title: FAU regulates carboplatin resistance in ovarian cancer.
abstract: The development of chemotherapy resistance by cancer cells is complex, using different mechanisms and pathways. The gene FAU (Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV)-associated ubiquitously expressed gene) was identified through functional expression cloning and previous data have shown that overexpression enhances apoptosis in several cell types. We demonstrate that the expression of FAU was reduced in the A2780cis (cisplatin resistant subclone of A2780) cell line compared with the A2780 ovarian cancer cell line, and was directly related to the cell line's sensitivity to carboplatin. Downregulation of FAU in the A2780 cell line by transfection with two predesigned short-interfering RNAs (siRNAs) to FAU resulted in a significant increase in resistance to carboplatin-induced cell death. Downregulation resulted in increased cell viability and reduced apoptosis after 72 hr of drug treatment compared with the negative controls (Kruskal-Wallis P = 0.0002). Transfection of the A2780cis cell line with the pcDNA3 plasmid containing FAU was associated with increased sensitivity to carboplatin-induced apoptosis, with decreased cell viability and increased apoptosis (Mann Whitney P < 0.0001). The expression of FAU was examined by quantitative real-time reverse transcriptase polymerase chain reaction in normal and malignant ovarian tissue. A significant reduction in the expression of FAU was seen in the malignant compared with normal ovarian samples (Kruskal-Wallis P = 0.0261). These data support a role for FAU in the regulation of platinum-resistance in ovarian cancer. Further research is needed into the apoptotic pathway containing FAU to investigate the potential for targeted therapies to increase or restore the platinum sensitivity of ovarian cancer.
authors.affiliation: Institute for Science and Technology in Medicine and School of Life Sciences, Keele University, Keele, UK. esther.moss@swbh.nhs.uk
authors.forename: Esther L
authors.initials: EL
authors.lastname: Moss
authors.forename: Mirna
authors.initials: M
authors.lastname: Mourtada-Maarabouni
authors.forename: Mark R
authors.initials: MR
authors.lastname: Pickard
authors.forename: Charles W
authors.initials: CW
authors.lastname: Redman
authors.forename: Gwyn T
authors.initials: GT
authors.lastname: Williams
mesh_terms: D017209:Apoptosis; D016190:Carboplatin / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D012269:Ribosomal Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D034741:RNA, Small Interfering; D012269:Ribosomal Proteins; C076845:FAU protein, human; D016190:Carboplatin