Pd51-07 Regulation of Glutamine Metabolism Resensitizes Tki-Resistant Renal Cancer Cells to Tkis

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology II (PD51)1 May 2024PD51-07 REGULATION OF GLUTAMINE METABOLISM RESENSITIZES TKI-RESISTANT RENAL CANCER CELLS TO TKIS Kento Morozumi, Yoshihide Kawasaki, Tomonori Sato, Shuichi Shimada, Takanari Sakai, Masamitsu Maekawa, Shinichi Yamashita, Nariyasu Mano, and Akihiro Ito Kento MorozumiKento Morozumi , Yoshihide KawasakiYoshihide Kawasaki , Tomonori SatoTomonori Sato , Shuichi ShimadaShuichi Shimada , Takanari SakaiTakanari Sakai , Masamitsu MaekawaMasamitsu Maekawa , Shinichi YamashitaShinichi Yamashita , Nariyasu ManoNariyasu Mano , and Akihiro ItoAkihiro Ito View All Author Informationhttps://doi.org/10.1097/01.JU.0001009360.84490.42.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Tyrosine Kinase Inhibitors (TKIs) play a significant role in combination with immunotherapy and in sequential treatment strategies. Effective use of TKI is a highly feasible method contributes to the prognosis of advanced renal cell carcinoma (RCC) patients. In a previous study, we found that glutamine metabolism is deeply involved in sunitinib (SU) resistance through metabolite analysis of urine from patients with SU failure and SU-resistant cells. This study aims to investigate antitumor effects to overcome TKI-resistance through the regulating cancer metabolism in RCC. METHODS: After establishing 3 cabozantinib (Cabo)-resistant RCC cell lines, we analyzed the antitumor effects of regulating glutamine metabolism by inhibiting glutaminase in vitro and in vivo. Moreover, we attempted to elucidate the mechanism of antitumor effects by regulating cancer metabolism in Cabo-resistant cells using VEGF signaling analyses in vitro and immunohistochemistry in vivo. RESULTS: The regulating glutamine metabolism demonstrated antitumor effects in all 3 Cabo-resistant cell lines both in vitro and in vivo. The regulating glutamine metabolism resulted in 35-55% cell-killing effect in 3 Cabo-resistant cell lines in vitro, and a maximum reduction of 66% was observed in vivo. We have found that the mechanism of TKI re-sensitivity caused by not only suppression of VEGF signaling (VEGFR2 and PI3K/AKT/HIF1 downregulation, and PTEN upregulation) through analyses of 3 Cabo-resistant cell lines, but also by angiogenesis inhibition through CD31 immunohistochemistry of Cabo-resistant grafts isolated from nude mice. CONCLUSIONS: Regulating glutamine metabolism has led to the effective use of TKIs, indicating the possibility of further improving the prognosis of advanced RCC patients resistant to TKIs. Download PPT Source of Funding: The authors declare no conflicts of interest © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e1067 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Kento Morozumi More articles by this author Yoshihide Kawasaki More articles by this author Tomonori Sato More articles by this author Shuichi Shimada More articles by this author Takanari Sakai More articles by this author Masamitsu Maekawa More articles by this author Shinichi Yamashita More articles by this author Nariyasu Mano More articles by this author Akihiro Ito More articles by this author Expand All Advertisement PDF downloadLoading ...