MP88-10 INHIBITION OF LIM AND SH3 DOMAIN PROTEIN 1 DELAYS CISPLATIN-RESISTANT BLADDER TUMOR PROGRESSION

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology IV1 Apr 2017MP88-10 INHIBITION OF LIM AND SH3 DOMAIN PROTEIN 1 DELAYS CISPLATIN-RESISTANT BLADDER TUMOR PROGRESSION Takashi Dejima, Ario Takeuchi, Masaki Shiota, Masatoshi Eto, Martin Gleave, and Christopher Ong Takashi DejimaTakashi Dejima More articles by this author , Ario TakeuchiArio Takeuchi More articles by this author , Masaki ShiotaMasaki Shiota More articles by this author , Masatoshi EtoMasatoshi Eto More articles by this author , Martin GleaveMartin Gleave More articles by this author , and Christopher OngChristopher Ong More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2735AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Bladder cancer is the 6th most common cancer in the USA. The current standard therapy for the first line of metastatic or local advanced bladder cancer is combination therapy with cisplatin (CDDP) and gemcitabine (GEM). However 5-years survival is still below 50%; therefore additional therapy is needed. LIM-SH3 domain protein 1 (LASP1), identified from cDNA library of metastatic axillary lymph nodes of breast cancer, has been shown to promote cancer progression and invasion in several malignancies. In bladder cancer, LASP1 expression associates with cell invasion and can be used for detecting bladder cancer. However, the anti-tumor effects of LASP1 knockdown in vivo as well as combination therapy with chemotherapy remain unclear. In this study, we investigated the anti-cancer activity of LASP1 knockdown in bladder cancer. METHODS LASP1 gene expression of tumor samples is analyzed using the Affymetrix Exon Array. The LASP1 expression in several bladder cancer cell lines was assessed by Western blot analysis and quantitative reverse transcription-PCR. Silencing of LASP1 in vitro was achieved using siRNA. Cell growth was measured by crystal violet assay. Cell cycle distribution was analyzed by flow cytometry after double thymidine block. The In vivo effect of LASP1 antisense oligonucleotide (ASO) treatment was assessed in the T24 CDDP-R (cisplatin-resistant) orthotopic bladder cancer model. RESULTS High LASP1 expression correlated with metastatic recurrence rate between patients. The LASP1 expression is higher in UC1 and T24 cells than in UC13 and UC6 cells. Knockdown of LASP1 using siRNA inhibited cell growth, and was accompanied by an increase in p21 and p27, and a decreased of cyclin D1. Flow cytometry revealed that LASP1 knockdown induced G1 arrest. Conversely, stable LASP1 overexpression drove cell growth with an increase of cyclin D1 in UC6 and UC3 cells. The treatment of CDDP and GEM induced LASP1 expression in Western Blotting. Furthermore, compared with parental cell line, LASP1 is higher in T24 CDDP-R and RT112 CDDP-R cells than in parental cells. LASP1 ASO inhibited cell growth in RT112 CDDP-R and T24 CDDP-R cells. In the orthotopic bladder cancer model, systemic LASP1 ASO administration to athymic nude mice delayed tumor progression in T24 CDDP-R cells. CONCLUSIONS These data revealed that LASP1 inhibition might be as a promising novel therapeutics modality in the treatment of chemoresistant bladder cancer. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1177-e1178 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Takashi Dejima More articles by this author Ario Takeuchi More articles by this author Masaki Shiota More articles by this author Masatoshi Eto More articles by this author Martin Gleave More articles by this author Christopher Ong More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...