Down-regulation of E-cadherin enhances prostate cancer chemoresistance via Notch signaling

Cancer Communications

Jian Zhang¹  Evan T. Keller¹  Wenchu Wang¹  Junlin Shi¹  Atsushi Mizokami²  Jinlu Dai³  Chunlin Zou⁴  Lihui Wang⁴  Yi Lu⁴ 

[1] Center for Translational Medicine, Guangxi Medical University, Nanning, P. R. China;Department of Urology and Pathology, School of Medicine, University of Michigan, Ann Arbor, USA;Department of Urology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan;Key Laboratory of Longevity and Ageing-related Diseases, Ministry of Education, Nanning, P. R. China

关键词: Epithelial-to-mesenchymal transition;    E-cadherin;    Chemoresistance;    Notch signaling;    Prostate cancer;   

DOI  :  10.1186/s40880-017-0203-x

学科分类：肿瘤学

来源: Springer

【 摘 要 】

The chemoresistance of prostate cancer (PCa) is invariably associated with the aggressiveness and metastasis of this disease. New emerging evidence indicates that the epithelial-to-mesenchymal transition (EMT) may play pivotal roles in the development of chemoresistance and metastasis. As a hallmark of EMT, E-cadherin is suggested to be a key marker in the development of chemoresistance. However, the molecular mechanisms underlying PCa chemoresistance remain unclear. The current study aimed to explore the association between EMT and chemoresistance in PCa as well as whether changing the expression of E-cadherin would affect PCa chemoresistance. Parental PC3 and DU145 cells and their chemoresistant PC3-TxR and DU145-TxR cells were analyzed. PC3-TxR and DU145-TxR cells were transfected with E-cadherin-expressing lentivirus to overexpress E-cadherin; PC3 and DU145 cells were transfected with small interfering RNA to silence E-cadherin. Changes of EMT phenotype-related markers and signaling pathways were assessed by Western blotting and quantitative real-time polymerase chain reaction. Tumor cell migration, invasion, and colony formation were then evaluated by wound healing, transwell, and colony formation assays, respectively. The drug sensitivity was evaluated using MTS assay. Chemoresistant PC3-TxR and DU145-TxR cells exhibited an invasive and metastatic phenotype that associated with EMT, including the down-regulation of E-cadherin and up-regulation of Vimentin, Snail, and N-cadherin, comparing with that of parental PC3 and DU145 cells. When E-cadherin was overexpressed in PC3-TxR and DU145-TxR cells, the expression of Vimentin and Claudin-1 was down-regulated, and tumor cell migration and invasion were inhibited. In particular, the sensitivity to paclitaxel was reactivated in E-cadherin-overexpressing PC3-TxR and DU145-TxR cells. When E-cadherin expression was silenced in parental PC3 and DU145 cells, the expression of Vimentin and Snail was up-regulated, and, particularly, the sensitivity to paclitaxel was decreased. Interestingly, Notch-1 expression was up-regulated in PC3-TxR and DU145-TxR cells, whereas the E-cadherin expression was down-regulated in these cells comparing with their parental cells. The use of γ-secretase inhibitor, a Notch signaling pathway inhibitor, significantly increased the sensitivity of chemoresistant cells to paclitaxel. The down-regulation of E-cadherin enhances PCa chemoresistance via Notch signaling, and inhibiting the Notch signaling pathway may reverse PCa chemoresistance.

【 授权许可】

CC BY