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Downregulation of DOCK1 sensitizes bladder cancer cells to cisplatin through preventing epithelial-mesenchymal
Da-Jin Chen1, Wei Chen2, Hong Jiang1
1Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine; Key Laboratory of Nephropathy; Kidney Disease Immunology Laboratory, The Third Grade Laboratory, State Administration of Traditional Chinese Medicine.
Abstract:
During the past several decades, resistance to single or multiple anticancer agents has posed a great challenge in cancer therapy. Dedicator of cytokinesis 1 (DOCK1), the first identified member in DOCK family, plays diverse roles in cellular processes, including tumorigenesis. In this study, we explored the biological role of DOCK1 in the chemotherapeutic resistance in bladder cancer and its underlying mechanism. Our results showed that the bladder cancer cell lines UM-UC-3 and J82 with higher DOCK1 are more resistant to cisplatin, whereas B87 cells with the lowest expression of DOCK1 exhibited the highest sensitivity to cisplatin. Down-regulation of DOCK1 with small interfering RNA (siRNA) increased the cisplatin sensitivity in bladder cancer cells. Moreover, treatment with cisplatin induced epithelial-mesenchymal transition (EMT), while transfection with Twist siRNA restored the chemosensitivity to cisplatin. In addition, we found that downregulation of DOCK1 reversed EMT program in bladder cancer cells. However, cotransfection with DOCK1 siRNA could not further enhance the cisplatin sensitivity and cellular phenotypic changes in tumor cells. Taken together, these results demonstrate that downregulation of DOCK1 could increase the chemosensitivity in bladder cancer cells via preventing cisplatin-induced EMT, suggesting that DOCK1 may serve as a potential therapeutic target in bladder cancer.
Insights
Dedicator of cytokinesis 1 (DOCK1) promotes bladder cancer resistance to cisplatin by inducing epithelial-mesenchymal transition (EMT). Downregulating DOCK1 enhances chemosensitivity, suggesting DOCK1 as a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Anticancer agent resistance is a major challenge in cancer therapy.
- Dedicator of cytokinesis 1 (DOCK1) is implicated in various cellular processes, including tumorigenesis.
Purpose of the Study:
- To investigate the role of DOCK1 in bladder cancer chemotherapeutic resistance.
- To elucidate the underlying mechanisms of DOCK1's involvement in cisplatin resistance.
Main Methods:
- Utilized bladder cancer cell lines with varying DOCK1 expression levels.
- Employed small interfering RNA (siRNA) to downregulate DOCK1 expression.
- Investigated the effects of cisplatin treatment and DOCK1 modulation on epithelial-mesenchymal transition (EMT).
Main Results:
- Higher DOCK1 expression correlated with increased cisplatin resistance in bladder cancer cells.
- DOCK1 downregulation via siRNA enhanced sensitivity to cisplatin.
- Cisplatin induced EMT, which was reversed by DOCK1 downregulation.
- Downregulating DOCK1 prevented cisplatin-induced EMT, restoring chemosensitivity.
Conclusions:
- DOCK1 downregulation increases chemosensitivity in bladder cancer by inhibiting cisplatin-induced EMT.
- DOCK1 represents a potential therapeutic target for overcoming cisplatin resistance in bladder cancer.
