MP92-11 TKI INDUCES GLUT1 EXPRESSION THROUGH IL-6 SECRETION ON RENAL CELL CARCINOMA CELLS

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology III1 Apr 2016MP92-11 TKI INDUCES GLUT1 EXPRESSION THROUGH IL-6 SECRETION ON RENAL CELL CARCINOMA CELLS Kei Ishibashi, Michihiro Yabe, Seiji Hoshi, Junya Hata, Hidenori Akaihata, Yuichi Sato, Soichiro Ogawa, Nobuhiro Haga, Nobuhiro Kushinda, Tomohiko Yanagida, Ken Aikawa, Joachim W Thüroff, Walburgis Brenner, and Yoshiyuki Kojima Kei IshibashiKei Ishibashi More articles by this author , Michihiro YabeMichihiro Yabe More articles by this author , Seiji HoshiSeiji Hoshi More articles by this author , Junya HataJunya Hata More articles by this author , Hidenori AkaihataHidenori Akaihata More articles by this author , Yuichi SatoYuichi Sato More articles by this author , Soichiro OgawaSoichiro Ogawa More articles by this author , Nobuhiro HagaNobuhiro Haga More articles by this author , Nobuhiro KushindaNobuhiro Kushinda More articles by this author , Tomohiko YanagidaTomohiko Yanagida More articles by this author , Ken AikawaKen Aikawa More articles by this author , Joachim W ThüroffJoachim W Thüroff More articles by this author , Walburgis BrennerWalburgis Brenner More articles by this author , and Yoshiyuki KojimaYoshiyuki Kojima More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2644AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Tyrosine-kinase inhibitors (TKI) treatment targeted at the vascular endothelial growth factor (VEGF) pathways represents the standard of care in advanced renal cell carcinoma (RCC). The TKI treatment has promising effect against RCC, however, the development of resistance to TKIs should be solved. We show that the autocrine secretion of IL-6 induced by TKIs-stimulation causes activation of AKT- mTOR pathway, and also show that combination therapy with IL-6 receptor antibody and TKI reduces angiogenesis and GLUT1 expression. METHODS Human renal cell carcinoma cell line 786-O was used for this study. Sorafenib, sunitinib and pazopanib were used as TKIs. GLUT1 expreiion and VEGF secretions from 786-O cells cultured with TKIs were measured by real time PCR and ELISA. Western blot analyses were applied for detection of GLUT1 as well as activated Akt, mTOR proteins. The growth of tumors in athymic mice receiving combination therapy with tocilizumab and sorafenib were compared with those in the sorafenib treated mice. The effects of the combination therapy were evaluated by FDG-PET and immunohistochemical examinations for CD31 and GLUT1. RESULTS The 786-O RCC cell line secreted IL-6 and VEGF when they were cultured with TKIs. Western blot analysis revealed that Akt and mTOR were phosphorylated by TKI treatment. Tocilizumab treatment in combination with TKIs reduced activation of IL-6 signaling pathway and also suppressed cell proliferation and GLUT1 expression. The mean SUV max was decreased on day 3 in athymic mice receiving combination therapy with tocilizumab and sorafenib in comparison with those in the sorafenib alone (9.8±1.6 vs. 11.5±0.8 respectively. p-0.04). No histopathological differences were found on day 3 despite decreased CD31 positive cells. On the day 21, the CD31 positive cells increased again in the tumors of sorafenib monotherapy. In contrast, when tocilizumab was given with sorafenib the tumor showed extensive central necrosis with absence of CD31 positive cells. CONCLUSIONS Our results indicate that TKI treatment induces GLUT1 expression on RCC cells. IL-6 antibody in combination with TIK would restrain angiogenesis and GLUT1 expression on RCC. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e1165-e1166 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Kei Ishibashi More articles by this author Michihiro Yabe More articles by this author Seiji Hoshi More articles by this author Junya Hata More articles by this author Hidenori Akaihata More articles by this author Yuichi Sato More articles by this author Soichiro Ogawa More articles by this author Nobuhiro Haga More articles by this author Nobuhiro Kushinda More articles by this author Tomohiko Yanagida More articles by this author Ken Aikawa More articles by this author Joachim W Thüroff More articles by this author Walburgis Brenner More articles by this author Yoshiyuki Kojima More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...