MP48-13 LOSS OF FORKHEAD BOX PROTEIN O1 (FOXO1) IN BLADDER CANCER INDUCES TUMOR PROGRESSION AS WELL AS CHEMORESISTANCE

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology II1 Apr 2017MP48-13 LOSS OF FORKHEAD BOX PROTEIN O1 (FOXO1) IN BLADDER CANCER INDUCES TUMOR PROGRESSION AS WELL AS CHEMORESISTANCE Hiroki Ide, Satoshi Inoue, Taichi Mizushima, Eiji Kashiwagi, Mototsugu Oya, Alexander Baras, and Hiroshi Miyamoto Hiroki IdeHiroki Ide More articles by this author , Satoshi InoueSatoshi Inoue More articles by this author , Taichi MizushimaTaichi Mizushima More articles by this author , Eiji KashiwagiEiji Kashiwagi More articles by this author , Mototsugu OyaMototsugu Oya More articles by this author , Alexander BarasAlexander Baras More articles by this author , and Hiroshi MiyamotoHiroshi Miyamoto More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1494AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Recent preclinical evidence has indicated the involvement of androgen receptor (AR) signals in bladder cancer outgrowth as well as chemosensitivity. Meanwhile, we have demonstrated that AR signals modulate the expression and activity of FOXO1, a transcriptional factor known to induce apoptosis through the PI3K-Akt pathway, in bladder cancer cells. In this study, we investigated the role of FOXO1 in bladder cancer progression as well as resistance to cisplatin treatment. METHODS We assessed the effects of FOXO1 inhibition via short hairpin RNA (shRNA) virus infection or inhibitor (AS1842856) treatment on bladder cancer cell proliferation (by MTT assay in the presence or absence of cisplatin), migration (by scratch wound healing assay), and invasion (by transwell invasion assay), apoptosis (by TUNEL assay), and the expression of their related molecules (by RT-PCR). We also immunohistochemically stained for phospho-FOXO1 (p-FOXO1), an inactive form of FOXO1, in tissue microarrays consisting of muscle-invasive bladder cancer specimens from patients who received at least 3 cycles of cisplatin + gemcitabine neoadjuvant chemotherapy prior to radical cystectomy. RESULTS FOXO1 silencing via its shRNA in AR-positive bladder cancer lines, UMUC3 and 647V-AR, resulted in significant increases in cell viability, migration, and invasion, and the expression of MMP-2/VEGF, as well as significant decreases in apoptosis and the expression of cyclin-dependent kinase inhibitors p21/p27. In addition, FOXO1 knockdown cells were significantly more resistant to cisplatin treatment at its pharmacological concentrations, compared with control cells. In these control FOXO1-positive lines, AS1842856 treatment also significantly reduced cisplatin sensitivity. Immunohistochemistry in transurethral resection specimens further showed p-FOXO1 positivity in 25 (58%) of 43 cases, including 7 (41%) of 17 responders to chemotherapy versus 18 (69%) of 26 non-responders (P=0.068). CONCLUSIONS FOXO1, as a tumor suppressor, appears to play an important role in bladder cancer progression and correlates with cisplatin sensitivity. Accordingly, FOXO1 stimulation, with or without AR inactivation, has the potential of being a therapeutic approach for bladder cancer and may also be useful for overcoming chemoresistance. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e641-e642 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Hiroki Ide More articles by this author Satoshi Inoue More articles by this author Taichi Mizushima More articles by this author Eiji Kashiwagi More articles by this author Mototsugu Oya More articles by this author Alexander Baras More articles by this author Hiroshi Miyamoto More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...