MP34-01 NICOTINE INDUCES TUMOR AGGRESSIVENESS AND CHEMORESISTANCE THROUGH ACTIVATION OF PI3K/AKT/MTOR PATHWAY IN BLADDER CANCER

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research III1 Apr 2014MP34-01 NICOTINE INDUCES TUMOR AGGRESSIVENESS AND CHEMORESISTANCE THROUGH ACTIVATION OF PI3K/AKT/MTOR PATHWAY IN BLADDER CANCER Kazuyuki Yuge, Eiji Kikuchi, Masayuki Hagiwara, Yota Yasumizu, Takeo Kosaka, Akira Miyajima, and Mototsugu Oya Kazuyuki YugeKazuyuki Yuge More articles by this author , Eiji KikuchiEiji Kikuchi More articles by this author , Masayuki HagiwaraMasayuki Hagiwara More articles by this author , Yota YasumizuYota Yasumizu More articles by this author , Takeo KosakaTakeo Kosaka More articles by this author , Akira MiyajimaAkira Miyajima More articles by this author , and Mototsugu OyaMototsugu Oya More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1014AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES It is unclear whether continued smoking after a diagnosis of bladder cancer is associated with a greater risk of tumor recurrence or progression. Recent basic studies suggest that nicotine is associated with tumor proliferation and angiogenesis in other types of cancers. However, the details of the signaling pathways by which nicotine could induce tumor aggressiveness are unknown. The aim of this study was to investigate whether nicotine could affect the signaling pathways in bladder cancer. METHODS Cell viability was evaluated in the human bladder cancer cell line T24 exposed to various concentrations of nicotine with or without CDDP and PI3K/mTOR dual inhibitor (PI3KI) treatment by WST-1 assay. Western blot analysis was performed to investigate the PI3K/Akt/mTOR (phosphorylated Akt: pAkt and S6: pS6) and MAPK pathways. In a subcutaneous bladder tumor model, mice received nicotine (1 mg/kg, i.p.) three times a week, or a single i.p. injection of CDDP (5 mg/kg) with or without daily p.o. administration of PI3KI (40 mg/kg). RESULTS The pAkt or pS6 pathway was significantly up-regulated in T24 cells after exposure to nicotine but no signal change was observed in the MAPK pathway. T24 cell growth was induced after exposure to 10µM of nicotine. In an in vivo study, tumor volume in mice given nicotine (929.1 mm3) was significantly increased as compared with that of the control mice (470.3 mm3)(p=0.039). In T24 cells exposed to 10µM of nicotine, pAkt or pS6 expression was increased and cell growth was not significantly inhibited by 5µM of CDDP treatment compared to T24 cells without nicotine exposure. Tumor volume in mice administered nicotine and CDDP (492.6 mm3) was significantly increased as compared with that in mice given CDDP alone (231.5 mm3)(p=0.010). Inhibition of cell growth was equal in cells with or without nicotine exposure and induced pAkt and pS6 activation by nicotine exposure was reduced by 500nM of PI3KI treatment. Tumor volume in mice administered nicotine and PI3KI (295.4 mm3) was not significantly increased as compared with that in mice given PI3KI alone (282.0 mm3) (p=0.923). CONCLUSIONS Nicotine increased tumor growth and was related to chemoresistance in bladder cancer. PI3K/mTOR inhibitors might be a potential therapeutic modality for treating bladder cancer patients who have been exposed to nicotine. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e362 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Kazuyuki Yuge More articles by this author Eiji Kikuchi More articles by this author Masayuki Hagiwara More articles by this author Yota Yasumizu More articles by this author Takeo Kosaka More articles by this author Akira Miyajima More articles by this author Mototsugu Oya More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...