title: Notch-1 signaling activates NF-κB in human breast carcinoma MDA-MB-231 cells via PP2A-dependent AKT pathway.
abstract: 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.
authors.affiliation: 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.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Niya
authors.initials: N
authors.lastname: Xiong
authors.affiliation: 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.
authors.forename: Shun
authors.initials: S
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: 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.|Center for Information in Biomedicine, University of Electronic Science and Technology of China, Chengdu, 610054, Sichuan, People's Republic of China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.affiliation: 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.|Center for Information in Biomedicine, University of Electronic Science and Technology of China, Chengdu, 610054, Sichuan, People's Republic of China.
authors.forename: Chunhui
authors.initials: C
authors.lastname: Wu
authors.affiliation: 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.|Center for Information in Biomedicine, University of Electronic Science and Technology of China, Chengdu, 610054, Sichuan, People's Republic of China.
authors.forename: Hongjuan
authors.initials: H
authors.lastname: Zeng
authors.affiliation: 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. liuyiyao@uestc.edu.cn.|Center for Information in Biomedicine, University of Electronic Science and Technology of China, Chengdu, 610054, Sichuan, People's Republic of China. liuyiyao@uestc.edu.cn.
authors.forename: Yiyao
authors.initials: Y
authors.lastname: Liu
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016328:NF-kappa B; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D054648:Protein Phosphatase 2; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: Invasion; NF-κB; Notch-1; PI3K/AKT; PP2A