1新光醫院 泌尿科，2中央研究室；3台北醫學大學 醫學院；4輔仁大學 醫學院
Hyperthermia Enhances Chemosensitivity of Bladder Cancer through Epithelial Mesenchymal Transition Suppression
Hung-En Chen 1, An-Chen Chang2, Te-Fu Tsai 1, Kuang-Yu Chou1, Chao-Yen Ho1, Peng-Hui Chang1and Thomas I-Sheng Hwang1,3,4
Department of Urology1 and Translational Medicine Center2, Shin Kong Wu Ho-Su Memorial Hospital; Department of Urology, Taipei Medical University3; Division of Urology, School of Medicine, Fu-Jen Catholic University4, Taipei, Taiwan.
Hyperthermia (HT), a non-invasive method of cancer treatment, kills the cancer cells and destroys nearby blood vessels by increasing tumor temperature. The intravesical chemotherapy has been widely used for bladder cancer (BC), but the development of acquired resistance remains a therapeutic hurdle. Cadherin-11 (CDH-11), a cell surface biomarker of epithelial cell-mesenchymal transition (EMT), plays an important role in cell survival and tumor growth. In this study, we aim to explore the mechanism of HT in inhibiting the action of EMT-mediated drug resistance and thus advantages intravesical chemotherapy in BC.
Materials and Methods:
The Cancer Cell Line Encyclopedia (CCLE), a database contains gene expression, genotype, and drug sensitivity data for human cancer cell lines, was used to screen EMT markers expression in BC cell lines RT4, 5637 and UMUC3. BC cells were treated with HT (43°C) for 24, 48 and 72 hours. Then, Western blot and qPCR were used to analyze the EMT-related proteins and their mRNA expression. Cell viability was assessed using resazurin reagent to detect whether HT reduces the chemotherapeutic drug resistance of BC cells.
The BC cells were treated with various concentrations of cisplatin for 24 h, and HT significantly reduced the viability of BC cells, indicating HT advanced chemosensitivity in BC. From CCLE database analysis, we found that mesenchymal markers, such as CDH-11, ZEB1/2, and snail, were overexpressed in bladder cancer cell UMUC3 (grade III) compared with RT4 (grade I) and 5637 (grade II). Upon HT stimulation, the UMUC3 cells underwent morphological changes from mesenchymal to epithelial, were observed low levels of CDH-11 mRNA and protein expression; however, ZEB1/2 and snail had no such effect. Knockdown of CDH-11 expression improved the chemosensitivity of BC cells to cisplatin, doxorubicin and epirubicin. We also discovered that β-catenin signaling pathway participated in the function of CDH-11-regulated chemosensitivity in BC.
Taken together, our study suggests that HT or co-targeting CDH-11 as a potential strategy to improve the therapeutic efficacy of intravesical chemotherapy in BC patients.