title: ABCF2, an Nrf2 target gene, contributes to cisplatin resistance in ovarian cancer cells.
abstract: Previously, we have demonstrated that NRF2 plays a key role in mediating cisplatin resistance in ovarian cancer. To further explore the mechanism underlying NRF2-dependent cisplatin resistance, we stably overexpressed or knocked down NRF2 in parental and cisplatin-resistant human ovarian cancer cells, respectively. These two pairs of stable cell lines were then subjected to microarray analysis, where we identified 18 putative NRF2 target genes. Among these genes, ABCF2, a cytosolic member of the ABC superfamily of transporters, has previously been reported to contribute to chemoresistance in clear cell ovarian cancer. A detailed analysis on ABCF2 revealed a functional antioxidant response element (ARE) in its promoter region, establishing ABCF2 as an NRF2 target gene. Next, we investigated the contribution of ABCF2 in NRF2-mediated cisplatin resistance using our stable ovarian cancer cell lines. The NRF2-overexpressing cell line, containing high levels of ABCF2, was more resistant to cisplatin-induced apoptosis compared to its control cell line; whereas the NRF2 knockdown cell line with low levels of ABCF2, was more sensitive to cisplatin treatment than its control cell line. Furthermore, transient overexpression of ABCF2 in the parental cells decreased apoptosis and increased cell viability following cisplatin treatment. Conversely, knockdown of ABCF2 using specific siRNA notably increased apoptosis and decreased cell viability in cisplatin-resistant cells treated with cisplatin. This data indicate that the novel NRF2 target gene, ABCF2, plays a critical role in cisplatin resistance in ovarian cancer, and that targeting ABCF2 may be a new strategy to improve chemotherapeutic efficiency.
authors.affiliation: Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.|Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, China.|Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
authors.forename: Lingjie
authors.initials: L
authors.lastname: Bao
authors.affiliation: Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.|Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, China.|Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
authors.forename: Jianfa
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona.
authors.forename: Matthew
authors.initials: M
authors.lastname: Dodson
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona.
authors.forename: Elisa Montserrat
authors.initials: EM
authors.lastname: Rojo de la Vega
authors.affiliation: Department of Pathology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ning
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Zhenbo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Yao
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona.
authors.forename: Donna D
authors.initials: DD
authors.lastname: Zhang
authors.affiliation: Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.|Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, China.|Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
authors.forename: Congjian
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.|Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, China.|Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
authors.forename: Xiaofang
authors.identifier: 0000-0001-8200-0861
authors.initials: X
authors.lastname: Yi
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D061745:Antioxidant Response Elements; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D010053:Ovary / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015854:Up-Regulation
chemical_list: C507640:ABCF2 protein, human; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D002945:Cisplatin
keywords: ABCF2; NRF2; chemoresistance; cisplatin; ovarian cancer