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MP49-09 ACTIVATION OF IFN/STAT1 SIGNALING IN CISPLATIN/GEMCITABINE RESISTANT BLADDER CANCER

2015; Lippincott Williams & Wilkins; Volume: 193; Issue: 4S Linguagem: Inglês

10.1016/j.juro.2015.02.513

1527-3792

Tetsutaro Hayashi, Roland Seiler, Robert H. Bell, S. Ettinger, Kendric Wang, Shannon Awrey, Kilian M. Gust, Wolfgang Jäger, Tilman Todenhoefer, Manuel Altamirano-Dimas, Akio Matsubara, Colin C. Collins, Peter C. Black,

Bladder and Urothelial Cancer Treatments

You have accessJournal of UrologyBladder Cancer: Basic Research III1 Apr 2015MP49-09 ACTIVATION OF IFN/STAT1 SIGNALING IN CISPLATIN/GEMCITABINE RESISTANT BLADDER CANCER Tetsutaro Hayashi, Roland Seiler, Robert H. Bell, Susan Ettinger, Kendric Wang, Shannon Awrey, Kilian Gust, Wolfgang Jäger, Tilman Todenhoefer, Manuel Altamirano-Dimas, Akio Matsubara, Colin Collins, and Peter Black Tetsutaro HayashiTetsutaro Hayashi More articles by this author , Roland SeilerRoland Seiler More articles by this author , Robert H. BellRobert H. Bell More articles by this author , Susan EttingerSusan Ettinger More articles by this author , Kendric WangKendric Wang More articles by this author , Shannon AwreyShannon Awrey More articles by this author , Kilian GustKilian Gust More articles by this author , Wolfgang JägerWolfgang Jäger More articles by this author , Tilman TodenhoeferTilman Todenhoefer More articles by this author , Manuel Altamirano-DimasManuel Altamirano-Dimas More articles by this author , Akio MatsubaraAkio Matsubara More articles by this author , Colin CollinsColin Collins More articles by this author , and Peter BlackPeter Black More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.513AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Cisplatin-based combination chemotherapy (CBCC) is the standard treatment for patients with advanced bladder cancer (BC). Although responses are observed in up to 60% of patients, these are rarely durable, and most patients with advanced BC succumb to their disease. In the neoadjuvant setting, approximately 40% of patients have a major response to CBCC, while the other 60% have no benefit and may even be harmed by the delay in definitive local therapy. In both settings predictive molecular markers are desirable for individualization of therapy, and novel targets are essential for designing new treatments. Here we aimed to identify a genomic signature associated with resistance to cisplatin (CDDP) and gemcitabine (GEM) in BC. METHODS Three chemosensitive BC cell lines (RT112, UM-UC3, UM-UC13) were treated serially with increasing concentrations of CDDP up to 10μM, 3.3μM, 3.3μM, or GEM up to 10μM, 10μM, 1μM, respectively in order to establish resistance (CDDP-R and GEM-R). Gene expression microarray analysis of the resistant cell lines compared to the sensitive parental lines was conducted on the Agilent SurePrint G3 Human GE 8x60K v2 Microarray. RESULTS We ranked the top differentially expressed genes between the parental chemosensitive cell lines and the derived chemoresistant cell lines. Genes related to interferon (IFN) signaling made up 21 of the top 100 and 10 of the top 15 up-regulated genes. Pathway analysis revealed that IFN/STAT1 signaling is activated in chemoresistant cell lines. With quantitative RT-PCR we confirmed that STAT1, IFITM1, IFI27, IFI44L, IFIT1 and OSA2 were up-regulated in chemoresistant cell lines. Knockdown of STAT1 in these chemoresistant cell lines decreased expression of IFITM1, IFI27, IFI44L, IFIT1 and OSA2 which are downstream target genes of IFN/STAT1 signaling. In addition, STAT1 depletion in chemoresistant cells partially restored chemotherapy sensitivity. CONCLUSIONS IFN/STAT1 signaling is activated in chemoresistant bladder cancer cell lines and its inhibition can re-sensitize to chemotherapy. These genes warrant further study for their potential as predictive markers and for rational co-targeting in the context of CBCC. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e606 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Tetsutaro Hayashi More articles by this author Roland Seiler More articles by this author Robert H. Bell More articles by this author Susan Ettinger More articles by this author Kendric Wang More articles by this author Shannon Awrey More articles by this author Kilian Gust More articles by this author Wolfgang Jäger More articles by this author Tilman Todenhoefer More articles by this author Manuel Altamirano-Dimas More articles by this author Akio Matsubara More articles by this author Colin Collins More articles by this author Peter Black More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...