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Title: Inhibition of disheveled-2 resensitizes cisplatin-resistant lung cancer cells through down-regulating Wnt/β-catenin signaling

Abstract

Cisplatin (CDDP) is currently recommended as the front-line chemotherapeutic agent for lung cancer. However, the resistance to cisplatin is widespread in patients with advanced lung cancer, and the molecular mechanism of such resistance remains incompletely understood. Disheveled (DVL), a key mediator of Wnt/β-catenin, has been linked to cancer progression, while the role of DVL in cancer drug resistance is not clear. Here, we found that DVL2 was over-expressed in cisplatin-resistant human lung cancer cells A549/CDDP compared to the parental A549 cells. Inhibition of DVL2 by its inhibitor (3289-8625) or shDVL2 resensitized A549/CDDP cells to cisplatin. In addition, over-expression of DVL2 in A549 cells increased the protein levels of BCRP, MRP4, and Survivin, which are known to be associated with chemoresistance, while inhibition of DVL2 in A549/CDDP cells decreased these protein levels, and reduced the accumulation and nuclear translocation of β-catenin. In addition, shβ-catenin abolished the DVL2-induced the expression of BCRP, MRP4, and Survivin. Furthermore, our data showed that GSK3β/β-catenin signals were aberrantly activated by DVL2, and inactivation of GSK3β reversed the shDVL2-induced down-regulation of β-catenin. Taken together, these results suggested that inhibition of DVL2 can sensitize cisplatin-resistant lung cancer cells through down-regulating Wnt/β-catenin signaling and inhibiting BCRP, MRP4, and Survivinmore » expression. It promises a new strategy to chemosensitize cisplatin-induced cytotoxicity in lung cancer. - Highlights: • Inhibition of DVL2 chemosensitizes resistant lung cancer to cisplatin. • DVL2 positively regulated the expression of BCRP, MRP4 and Survivin. • β-catenin mediated the DVL2-induced expression. • DVL2 increased the accumulation and nuclear translocation of β-catenin. • DVL2 up-regulated β-catenin via inhibiting GSK3β.« less

Authors:
;  [1]; ; ; ; ;  [2]; ;  [1]; ;  [2];  [2];  [3];  [2]
  1. School of Basic Medical Sciences, Chengdu Medical College, Chengdu (China)
  2. School of Biomedical Sciences, Chengdu Medical College, Chengdu (China)
  3. Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital, Chengdu Medical College, Chengdu (China)
Publication Date:
OSTI Identifier:
22649756
Resource Type:
Journal Article
Resource Relation:
Journal Name: Experimental Cell Research; Journal Volume: 347; Journal Issue: 1; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BUILDUP; DRUGS; INACTIVATION; INHIBITION; LUNGS; NEOPLASMS; PATIENTS; PLATINUM COMPLEXES; PROTEINS; SIGNALS; TOXICITY; TRANSLOCATION

Citation Formats

Luo, Ke, Gu, Xiuhui, Liu, Jing, Zeng, Guodan, Peng, Liaotian, Huang, Houyi, Jiang, Mengju, Yang, Ping, Li, Minhui, Yang, Yuhan, Wang, Yuanyuan, Peng, Quekun, E-mail: pengquekun@163.com, Zhu, Li, E-mail: 1968403299@qq.com, and Zhang, Kun, E-mail: zhangkunyyo@163.com. Inhibition of disheveled-2 resensitizes cisplatin-resistant lung cancer cells through down-regulating Wnt/β-catenin signaling. United States: N. p., 2016. Web. doi:10.1016/J.YEXCR.2016.07.014.
Luo, Ke, Gu, Xiuhui, Liu, Jing, Zeng, Guodan, Peng, Liaotian, Huang, Houyi, Jiang, Mengju, Yang, Ping, Li, Minhui, Yang, Yuhan, Wang, Yuanyuan, Peng, Quekun, E-mail: pengquekun@163.com, Zhu, Li, E-mail: 1968403299@qq.com, & Zhang, Kun, E-mail: zhangkunyyo@163.com. Inhibition of disheveled-2 resensitizes cisplatin-resistant lung cancer cells through down-regulating Wnt/β-catenin signaling. United States. doi:10.1016/J.YEXCR.2016.07.014.
Luo, Ke, Gu, Xiuhui, Liu, Jing, Zeng, Guodan, Peng, Liaotian, Huang, Houyi, Jiang, Mengju, Yang, Ping, Li, Minhui, Yang, Yuhan, Wang, Yuanyuan, Peng, Quekun, E-mail: pengquekun@163.com, Zhu, Li, E-mail: 1968403299@qq.com, and Zhang, Kun, E-mail: zhangkunyyo@163.com. Sat . "Inhibition of disheveled-2 resensitizes cisplatin-resistant lung cancer cells through down-regulating Wnt/β-catenin signaling". United States. doi:10.1016/J.YEXCR.2016.07.014.
@article{osti_22649756,
title = {Inhibition of disheveled-2 resensitizes cisplatin-resistant lung cancer cells through down-regulating Wnt/β-catenin signaling},
author = {Luo, Ke and Gu, Xiuhui and Liu, Jing and Zeng, Guodan and Peng, Liaotian and Huang, Houyi and Jiang, Mengju and Yang, Ping and Li, Minhui and Yang, Yuhan and Wang, Yuanyuan and Peng, Quekun, E-mail: pengquekun@163.com and Zhu, Li, E-mail: 1968403299@qq.com and Zhang, Kun, E-mail: zhangkunyyo@163.com},
abstractNote = {Cisplatin (CDDP) is currently recommended as the front-line chemotherapeutic agent for lung cancer. However, the resistance to cisplatin is widespread in patients with advanced lung cancer, and the molecular mechanism of such resistance remains incompletely understood. Disheveled (DVL), a key mediator of Wnt/β-catenin, has been linked to cancer progression, while the role of DVL in cancer drug resistance is not clear. Here, we found that DVL2 was over-expressed in cisplatin-resistant human lung cancer cells A549/CDDP compared to the parental A549 cells. Inhibition of DVL2 by its inhibitor (3289-8625) or shDVL2 resensitized A549/CDDP cells to cisplatin. In addition, over-expression of DVL2 in A549 cells increased the protein levels of BCRP, MRP4, and Survivin, which are known to be associated with chemoresistance, while inhibition of DVL2 in A549/CDDP cells decreased these protein levels, and reduced the accumulation and nuclear translocation of β-catenin. In addition, shβ-catenin abolished the DVL2-induced the expression of BCRP, MRP4, and Survivin. Furthermore, our data showed that GSK3β/β-catenin signals were aberrantly activated by DVL2, and inactivation of GSK3β reversed the shDVL2-induced down-regulation of β-catenin. Taken together, these results suggested that inhibition of DVL2 can sensitize cisplatin-resistant lung cancer cells through down-regulating Wnt/β-catenin signaling and inhibiting BCRP, MRP4, and Survivin expression. It promises a new strategy to chemosensitize cisplatin-induced cytotoxicity in lung cancer. - Highlights: • Inhibition of DVL2 chemosensitizes resistant lung cancer to cisplatin. • DVL2 positively regulated the expression of BCRP, MRP4 and Survivin. • β-catenin mediated the DVL2-induced expression. • DVL2 increased the accumulation and nuclear translocation of β-catenin. • DVL2 up-regulated β-catenin via inhibiting GSK3β.},
doi = {10.1016/J.YEXCR.2016.07.014},
journal = {Experimental Cell Research},
number = 1,
volume = 347,
place = {United States},
year = {Sat Sep 10 00:00:00 EDT 2016},
month = {Sat Sep 10 00:00:00 EDT 2016}
}