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.
Highlights
Transition cell carcinoma (TCC) is one of the most deadly cancers worldwide, advanced stages of transitional cell carcinoma (TCC) [1]
Patients with locally advanced bladder cancer are still at high risk for metastases. Conventional cytotoxic chemotherapy such as platinum based combination chemotherapy is commonly used as a main regimen for advanced stages of TCC, which currently provides the potential for cure only in selected patients and is underpowered [2]
By delineating its mechanism of action, we demonstrated that CYD 6-17 was able to suppress Wnt pathway by targeting β-catenin expression that has been shown to be associated with chemo-resistance of TCC and other cancers [11,12,13,14,15,16,17,18]
Summary
Transition cell carcinoma (TCC) is one of the most deadly cancers worldwide, advanced stages of TCC [1]. Patients with locally advanced bladder cancer are still at high risk for metastases. Conventional cytotoxic chemotherapy such as platinum based combination chemotherapy is commonly used as a main regimen for advanced stages of TCC, which currently provides the potential for cure only in selected patients and is underpowered [2]. Only small improvement on the overall survival of patients has been made in the treatment of advanced TCC over the past decade, and the long-term survival remains low [3]. It is imperative to identify specific pathway(s) or molecular target(s) associated with advanced TCC that can achieve better therapeutic efficacy, while decreasing the morbidity and mortality related to TCC
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