Targeting XBP1-mediated β-catenin expression associated with bladder cancer with newly synthetic Oridonin analogues
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Wei Chen1,2,*, Jiancheng Zhou3,*, Kaijie Wu1, Jun Huang1, Ye Ding4, Eun-Jin Yun2, Bin Wang1,2, Chunyong Ding4, Elizabeth Hernandez2, John Santoyo2, Haiying Chen4, Ho Lin5, Arthur Sagalowsky2, Dalin He1, Jia Zhou4, Jer-Tsong Hsieh2,6
1Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710049, China
2Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
3Department of Urology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
4Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA
5Department of Life Sciences, National Chung Hsing University, Taichung 40705, Taiwan
6Graduate Institute of Cancer Biology, China Medical University Hospital, Taichung 40447, Taiwan
*These authors have contributed equally to this work
Jer-Tsong Hsieh, email: firstname.lastname@example.org
Jia Zhou, email: email@example.com
Dalin He, email: firstname.lastname@example.org
Keywords: Oridonin, Wnt pathway, β-catenin, XBP1, transitional cell carcinoma
Received: May 11, 2016 Accepted: July 01, 2016 Published: July 27, 2016
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.
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