TY - JOUR
T1 - Targeting XBP1-mediated β-catenin expression associated with bladder cancer with newly synthetic Oridonin analogues
AU - Chen, Wei
AU - Zhou, Jiancheng
AU - Wu, Kaijie
AU - Huang, Jun
AU - Ding, Ye
AU - Yun, Eun Jin
AU - Wang, Bin
AU - Ding, Chunyong
AU - Hernandez, Elizabeth
AU - Santoyo, John
AU - Chen, Haiying
AU - Lin, Ho
AU - Sagalowsky, Arthur I
AU - He, Dalin
AU - Zhou, Jia
AU - Hsieh, Jer-Tsong
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Oridonin
KW - Transitional cell carcinoma
KW - Wnt pathway
KW - XBP1
KW - β-catenin
UR - http://www.scopus.com/inward/record.url?scp=84984878615&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84984878615&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.10863
DO - 10.18632/oncotarget.10863
M3 - Article
C2 - 27472396
AN - SCOPUS:84984878615
SN - 1949-2553
VL - 7
SP - 56842
EP - 56854
JO - Oncotarget
JF - Oncotarget
IS - 35
ER -