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: Hao Liu, Yixue Gu, Jiang Yin, Guopei Zheng, Chenkun Wang, Zhijie Zhang, Min Deng, Jifang Liu, Xiaoting Jia, Zhimin He
• Journal: Cellular signalling (Cell Signal) Vol. 26 Issue 12 Pg. 2710-20 (Dec 2014) ISSN: 1873-3913 [Electronic] England
• PMID: 25152373 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Cell Cycle Proteins
• DNA-Binding Proteins
• Histone Chaperones
• Intracellular Signaling Peptides and Proteins
• MYC protein, human
• N-myc downstream-regulated gene 1 protein
• Proto-Oncogene Proteins c-myc
• SET protein, human
• Transcription Factors
• Cisplatin

Topics

• Animals
• Antineoplastic Agents
• Cell Cycle Proteins (metabolism)
• Cell Line, Tumor
• Cisplatin (pharmacology)
• DNA-Binding Proteins
• Drug Resistance, Neoplasm (physiology)
• Epithelial-Mesenchymal Transition (drug effects, physiology)
• Histone Chaperones (metabolism)
• Humans
• Intracellular Signaling Peptides and Proteins (metabolism)
• Lung Neoplasms
• Mice
• Phenotype
• Proto-Oncogene Proteins c-myc (metabolism)
• Signal Transduction (physiology)
• Transcription Factors (metabolism)