CDK4/6 Inhibition Controls Proliferation of Bladder Cancer and Transcription of RB1

视网膜母细胞瘤 癌症研究 视网膜母细胞瘤蛋白 细胞周期 医学 膀胱癌 癌症 顺铂 细胞周期蛋白D1 E2F型 细胞凋亡 E2F1 细胞生长 生物 内科学 基因 化疗 遗传学
作者
Anuja Sathe,Nicole Rachel Koshy,Sebastian C. Schmid,Mark Thalgott,Sarah M. Schwarzenböck,Bernd J. Krause,Per Sonne Holm,Juergen E. Gschwend,Margitta Retz,Roman Nawroth
出处
期刊:The Journal of Urology [Lippincott Williams & Wilkins]
卷期号:195 (3): 771-779 被引量:46
标识
DOI:10.1016/j.juro.2015.08.082
摘要

The retinoblastoma signaling network is frequently altered in advanced bladder cancer. We investigated the potential of CDK4/6 as a therapeutic target and determined biomarkers for patient stratification.Genetic alterations were analyzed using public databases, including TCGA (The Cancer Genome Atlas), COSMIC (Catalogue of Somatic Mutations in Cancer) and CCLE (Cancer Cell Line Encyclopedia). Effects of the CDK4/6-inhibitor PD-0332991 or LY2835219 were examined in 10 bladder cancer cell lines by immunoblot, cell viability, apoptosis and cell cycle progression. Efficacy of the PD-0332991 and cisplatin combination was analyzed using the combination index. Gene expression level was determined by quantitative polymerase chain reaction. Cytomegalovirus promoter regulated recombinant retinoblastoma was used for reconstitution. Three-dimensional xenografts were grown on chicken chorioallantoic membrane and analyzed by measuring tumor weight and immunohistochemical expression of total retinoblastoma and Ki-67.PD-0332991 treatment decreased the proliferation of retinoblastoma positive bladder cancer cell lines and was synergistic in combination with cisplatin. PD-0332991 or LY2835219 treatment decreased the phosphorylation, total protein and transcript level of retinoblastoma. Treatment resulted in a decrease in E2F target gene expression (CCNA2 and CCNE2) and cell cycle progression from G0/G1 to the S-phase but did not affect apoptosis. In retinoblastoma negative cells reconstituted with recombinant retinoblastoma PD-0332991 affected only phosphorylation and not the total retinoblastoma level. These cells remained resistant to treatment. In 3-dimensional retinoblastoma xenografts, treatment resulted in reduced tumor weight and decreased expression of total retinoblastoma and Ki-67.We provide preclinical evidence that CDK4/6 inhibition is a potential therapeutic strategy for retinoblastoma positive bladder cancer that probably acts by negatively regulating retinoblastoma transcription.
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