title: Ascites Increases Expression/Function of Multidrug Resistance Proteins in Ovarian Cancer Cells.
abstract: Chemotherapy resistance is the major reason for the failure of ovarian cancer treatment. One mechanism behind chemo-resistance involves the upregulation of multidrug resistance (MDR) genes (ABC transporters) that effectively transport (efflux) drugs out of the tumor cells. As a common symptom in stage III/IV ovarian cancer patients, ascites is associated with cancer progression. However, whether ascites drives multidrug resistance in ovarian cancer cells awaits elucidation. Here, we demonstrate that when cultured with ascites derived from ovarian cancer-bearing mice, a murine ovarian cancer cell line became less sensitive to paclitaxel, a first line chemotherapeutic agent for ovarian cancer patients. Moreover, incubation of murine ovarian cancer cells in vitro with ascites drives efflux function in these cells. Functional studies show ascites-driven efflux is suppressible by specific inhibitors of either of two ABC transporters [Multidrug Related Protein (MRP1); Breast Cancer Related Protein (BCRP)]. To demonstrate relevance of our findings to ovarian cancer patients, we studied relative efflux in human ovarian cancer cells obtained from either patient ascites or from primary tumor. Immortalized cell lines developed from human ascites show increased susceptibility to efflux inhibitors (MRP1, BCRP) compared to a cell line derived from a primary ovarian cancer, suggesting an association between ascites and efflux function in human ovarian cancer. Efflux in ascites-derived human ovarian cancer cells is associated with increased expression of ABC transporters compared to that in primary tumor-derived human ovarian cancer cells. Collectively, our findings identify a novel activity for ascites in promoting ovarian cancer multidrug resistance.
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina, 27710, United States of America.
authors.forename: Lihong
authors.initials: L
authors.lastname: Mo
authors.affiliation: Faculty of Science, Masaryk University, Kotlarska 2, 61137, Brno, Czech Republic.
authors.forename: Vendula
authors.initials: V
authors.lastname: Pospichalova
authors.affiliation: Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina, 27710, United States of America.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina, 27710, United States of America; Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina, 27710, United States of America.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Murphy
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina, 27710, United States of America.
authors.forename: Sturgis
authors.initials: S
authors.lastname: Payne
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina, 27710, United States of America.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina, 27710, United States of America.
authors.forename: Margaret
authors.initials: M
authors.lastname: Kennedy
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina, 27710, United States of America.
authors.forename: George J
authors.initials: GJ
authors.lastname: Cianciolo
authors.affiliation: Faculty of Science, Masaryk University, Kotlarska 2, 61137, Brno, Czech Republic.
authors.forename: Vitezslav
authors.initials: V
authors.lastname: Bryja
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina, 27710, United States of America.
authors.forename: Salvatore V
authors.initials: SV
authors.lastname: Pizzo
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina, 27710, United States of America.
authors.forename: Robin E
authors.initials: RE
authors.lastname: Bachelder
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001201:Ascites / Q000473:pathology*; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology; D005260:Female; D019450:Genes, MDR / Q000187:drug effects; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D017239:Paclitaxel