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Activation of nuclear PTEN by inhibition of Notch signaling induces G2/M cell cycle arrest in gastric cancer

 S-J Kim  ;  H-W Lee  ;  J-H Baek  ;  Y-H Cho  ;  HG Kang  ;  JS Jeong  ;  J Song  ;  H-S Park  ;  K-H Chun 
 ONCOGENE, Vol.35(2) : 251-260, 2016 
Journal Title
Issue Date
Animals ; Apoptosis/drug effects ; Apoptosis/genetics ; Cell Line, Tumor ; Cell Nucleus/metabolism ; Cyclin B1/metabolism ; Female ; G2 Phase Cell Cycle Checkpoints/drug effects ; Gene Expression Regulation, Neoplastic ; Humans ; Mice, Inbred BALB C ; Oligopeptides/pharmacology ; PTEN Phosphohydrolase/genetics ; PTEN Phosphohydrolase/metabolism* ; Phosphorylation ; Receptor, Notch1/genetics ; Receptor, Notch1/metabolism ; Receptors, Notch/genetics ; Receptors, Notch/metabolism* ; Signal Transduction ; Stomach Neoplasms/drug therapy ; Stomach Neoplasms/metabolism* ; Stomach Neoplasms/mortality ; Stomach Neoplasms/pathology* ; Xenograft Model Antitumor Assays
Mutation in PTEN has not yet been detected, but its function as a tumor suppressor is inactivated in many cancers. In this study we determined that, activated Notch signaling disables PTEN by phosphorylation and thereby contributes to gastric tumorigenesis. Notch inhibition by small interfering RNA or γ-secretase inhibitor (GSI) induced mitotic arrest and apoptosis in gastric cancer cells. Notch inhibition induced dephosphorylation in the C-terminal domain of PTEN, which led to PTEN nuclear localization. Overexpression of activated Notch1-induced phosphorylation of PTEN and reversed GSI-induced mitotic arrest. Dephosphorylated nuclear PTEN caused prometaphase arrest by interaction with the cyclin B1-CDK1 complex, resulting in their accumulation in the nucleus and subsequent apoptosis. We found a correlation between high expression levels of Notch1 and low survival rates and, similarly, between reduced nuclear PTEN expression and increasing the TNM classification of malignant tumours stages in malignant tissues from gastric cancer patients. The growth of Notch1-depleted gastric tumors was significantly retarded in xenografted mice, and in addition, PTEN deletion restored growth similar to control tumors. We also demonstrated that combination treatment with GSI and chemotherapeutic agents significantly reduced the orthotopically transplanted gastric tumors in mice without noticeable toxicity. Overall, our findings suggest that inhibition of Notch signaling can be employed as a PTEN activator, making it a potential target for gastric cancer therapy.
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1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Seok Jun(김석준)
Chun, Kyung Hee(전경희) ORCID logo https://orcid.org/0000-0002-9867-7321
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