title: SET-mediated NDRG1 inhibition is involved in acquisition of epithelial-to-mesenchymal transition phenotype and cisplatin resistance in human lung cancer cell.
abstract: Development of resistance to therapy continues to be a serious clinical problem in lung cancer management. Cancer cells undergoing epithelial-to-mesenchymal transition (EMT) have been shown to play roles in resistance to chemotherapy. Here, we utilized a proteomics-based method and identified a significant downregulation of the metastasis suppressor NDRG1 in drug resistant lung cancer cells. We showed that downregulation of DNRG1 constitutes a mechanism for acquisition of EMT phenotype and endows lung cancer cells with an increased resistance to cisplatin. We also identified a signal cascade, namely, SET--| PP2A--| c-myc--| NDRG1, in which upregulation of SET is critical for inhibition of NDRG1. We also found that blockade of SET (or reactivation of PP2A) by FTY720 reverted EMT, restored drug sensitivity, and inhibited invasiveness and growth of lung tumor xenografts. Together, our results indicated a functional link between SET-mediated NDRG1 regulation and acquisition of EMT phenotype and drug resistance, and provided an evidence that blockade of SET-driven EMT can overcome drug resistance and inhibit tumor progression.
authors.affiliation: Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.affiliation: Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, China.
authors.forename: Yixue
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Yin
authors.affiliation: Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, China.
authors.forename: Guopei
authors.initials: G
authors.lastname: Zheng
authors.affiliation: Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, China.
authors.forename: Chenkun
authors.initials: C
authors.lastname: Wang
authors.affiliation: Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, China.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, China.
authors.forename: Min
authors.initials: M
authors.lastname: Deng
authors.affiliation: Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, China.
authors.forename: Jifang
authors.initials: J
authors.lastname: Liu
authors.affiliation: Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, China.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Jia
authors.affiliation: Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, China. Electronic address: hezhimin2005@yahoo.com.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: He
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000502:physiology*; D056488:Histone Chaperones / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008175:Lung Neoplasms; D051379:Mice; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D002945:Cisplatin; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D047908:Intracellular Signaling Peptides and Proteins; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C489427:MYC protein, human; C513473:SET protein, human
keywords: Drug resistance; EMT; Lung cancer; NDRG1; SET