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 Survivin expression. It promises a new strategy to chemosensitize cisplatin-induced cytotoxicity in lung cancer.
authors.affiliation: School of Basic Medical Sciences, Chengdu Medical College, Chengdu, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Luo
authors.affiliation: School of Basic Medical Sciences, Chengdu Medical College, Chengdu, China.
authors.forename: Xiuhui
authors.initials: X
authors.lastname: Gu
authors.affiliation: School of Biomedical Sciences, Chengdu Medical College, Chengdu, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: School of Biomedical Sciences, Chengdu Medical College, Chengdu, China.
authors.forename: Guodan
authors.initials: G
authors.lastname: Zeng
authors.affiliation: School of Biomedical Sciences, Chengdu Medical College, Chengdu, China.
authors.forename: Liaotian
authors.initials: L
authors.lastname: Peng
authors.affiliation: School of Biomedical Sciences, Chengdu Medical College, Chengdu, China.
authors.forename: Houyi
authors.initials: H
authors.lastname: Huang
authors.affiliation: School of Biomedical Sciences, Chengdu Medical College, Chengdu, China.
authors.forename: Mengju
authors.initials: M
authors.lastname: Jiang
authors.affiliation: School of Basic Medical Sciences, Chengdu Medical College, Chengdu, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.affiliation: School of Basic Medical Sciences, Chengdu Medical College, Chengdu, China.
authors.forename: Minhui
authors.initials: M
authors.lastname: Li
authors.affiliation: School of Biomedical Sciences, Chengdu Medical College, Chengdu, China.
authors.forename: Yuhan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: School of Biomedical Sciences, Chengdu Medical College, Chengdu, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Biomedical Sciences, Chengdu Medical College, Chengdu, China. Electronic address: pengquekun@163.com.
authors.forename: Quekun
authors.initials: Q
authors.lastname: Peng
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital, Chengdu Medical College, Chengdu, China. Electronic address: 1968403299@qq.com.
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.affiliation: School of Biomedical Sciences, Chengdu Medical College, Chengdu, China. Electronic address: zhangkunyyo@163.com.
authors.forename: Kun
authors.initials: K
authors.lastname: Zhang
mesh_terms: D000072283:A549 Cells; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D000072261:Dishevelled Proteins / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000072261:Dishevelled Proteins; D009363:Neoplasm Proteins; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; D002945:Cisplatin
keywords: Cisplatin; Disheveled; Lung cancer; Resistance; Wnt/β-catenin