Notch-1 signaling activates NF-κB in human breast carcinoma MDA-MB-231 cells via PP2A-dependent AKT pathway

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• 作者：Li Li ; Jing Zhang ; Niya Xiong ; Shun Li ; Yu Chen ; Hong Yang ; Chunhui Wu…
• 关键词：Notch ; 1 ; NF ; κB ; PP2A ; Invasion ; PI3K/AKT
• 刊名：Medical Oncology
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：33
• 期：4
• 全文大小：2,204 KB
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• 作者单位：Li Li (1)
  Jing Zhang (1)
  Niya Xiong (1)
  Shun Li (1)
  Yu Chen (1)
  Hong Yang (1) (2)
  Chunhui Wu (1) (2)
  Hongjuan Zeng (1) (2)
  Yiyao Liu (1) (2)
  
  1. Department of Biophysics, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 610054, Sichuan, People’s Republic of China
  2. Center for Information in Biomedicine, University of Electronic Science and Technology of China, Chengdu, 610054, Sichuan, People’s Republic of China
  
• 刊物主题：Oncology; Hematology; Pathology; Internal Medicine;
• 出版者：Springer US
• ISSN：1559-131X

文摘

Breast cancer has a high incidence in the world and is becoming a leading cause of death in female patients due to its high metastatic ability. High expression of Notch-1 and its ligand Jagged-1 correlates with poor prognosis in breast cancer. Our previous work has shown that Notch-1 signaling pathway upregulates NF-κB transcriptional activity and induces the adhesion, migration and invasion of human breast cancer cell line MDA-MB-231. However, the role of Notch-1 in NF-κB activation is still poorly understood. Here, we aim to understand the exact mechanism that Notch-1 regulates NF-κB activity. In MDA-MB-231 cells where Notch-1 is constitutively activated, the phosphorylation of p85 and AKT (Tyr308/Ser473) is upregulated, indicating PI3K/AKT pathway is activated. Notch-1 activation caused the increase of PP2A phosphorylation at Tyr307, indicating Notch-1 inhibits PP2A activity. NF-κB transcriptional activity was evaluated by dual-luciferase reporter assay, and the results showed that, while silencing of Notch-1, PP2A activity was upregulated and NF-κB activity was downregulated, whereas PP2A inhibitor okadaic acid (OA) restored NF-κB activity. Immunofluorescence and Western blots showed that OA treatment antagonized the decrease of p65 nuclear translocation caused by Notch-1 silencing. Moreover, OA treatment also upregulated MMP-2, MMP-9 and VEGF mRNA expression levels, indicating OA rescues Notch-1 silencing that caused low cell invasion. Taken together, our results suggest that Notch-1-activating PI3K/AKT/NF-κB pathway is PP2A dependent; PP2A may be a potential therapeutic target in breast cancer.