title: Targeting XBP1-mediated β-catenin expression associated with bladder cancer with newly synthetic Oridonin analogues.
abstract: 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.
authors.affiliation: Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710049, China.|Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Urology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China.
authors.forename: Jiancheng
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710049, China.
authors.forename: Kaijie
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710049, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Eun-Jin
authors.initials: EJ
authors.lastname: Yun
authors.affiliation: Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710049, China.|Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Chunyong
authors.initials: C
authors.lastname: Ding
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hernandez
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: John
authors.initials: J
authors.lastname: Santoyo
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Haiying
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Life Sciences, National Chung Hsing University, Taichung 40705, Taiwan.
authors.forename: Ho
authors.initials: H
authors.lastname: Lin
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Sagalowsky
authors.affiliation: Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710049, China.
authors.forename: Dalin
authors.initials: D
authors.lastname: He
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.|Graduate Institute of Cancer Biology, China Medical University Hospital, Taichung 40447, Taiwan.
authors.forename: Jer-Tsong
authors.initials: JT
authors.lastname: Hsieh
mesh_terms: D000818:Animals; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019295:Computational Biology; D045786:Diterpenes, Kaurane / Q000737:chemistry / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism; D000071717:X-Box Binding Protein 1 / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; D045786:Diterpenes, Kaurane; D051153:Wnt Proteins; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D051176:beta Catenin; C011959:oridonin
keywords: Oridonin; Wnt pathway; XBP1; transitional cell carcinoma; β-catenin