Conventional chemotherapy is commonly used for advanced stages of transitional cell carcinoma (TCC) with modest success and high morbidity; however, TCC eventually develops resistance. Muscle invasive bladder cancer (MIBC) is recognized as a lethal disease due to its poor response to traditional chemotherapy. Numerous studies have implicated β-catenin, a critical effector in Wnt-mediated pathway associated with epithelial-mesenchymal transition and cancer stem cell, is involved in TCC progression, and furthermore closely associated with chemo-resistance. In this study, we discovered a novel natural product analogue CYD 6-17 that has a potent inhibitory effect on TCC cells exhibiting drug resistance to various chemotherapeutics, with an IC50 at nM range. Delivery of CYD 6-17 significantly inhibited the tumor growth using xenograft model but without detectable side effects. Mechanistically, it targeted β-catenin gene transcription by decreasing the binding of XBP1 to the promoter region, which appeared to be a new regulatory mechanism for β-catenin gene expression. Clinically, XBP1 expression correlated with the poor overall survival of patients. Overall, this study unveils unique mechanism of β-catenin gene regulation in advanced TCC and also offers a potential rational therapeutic regimen to MIBC.
Oncotarget. 2016 Jul 27 [Epub ahead of print]
Wei Chen, Jiancheng Zhou, Kaijie Wu, Jun Huang, Ye Ding, Eun-Jin Yun, Bin Wang, Chunyong Ding, Elizabeth Hernandez, John Santoyo, Haiying Chen, Ho Lin, Arthur Sagalowsky, Dalin He, Jia Zhou, Jer-Tsong Hsieh
Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710049, China., Department of Urology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China., Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710049, China., Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710049, China., Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA., Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710049, China., Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA., Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA., Department of Life Sciences, National Chung Hsing University, Taichung 40705, Taiwan., Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710049, China., Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA., Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.