title: Activation of nuclear PTEN by inhibition of Notch signaling induces G2/M cell cycle arrest in gastric cancer.
abstract: 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.
authors.affiliation: Department of Biochemistry & Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea.|Brain Korea 21 PLUS Project for Medical Sciences, Severance Medical Research Institute, Seoul, Republic of Korea.
authors.forename: S-J
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Biochemistry & Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea.|Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors.forename: H-W
authors.initials: HW
authors.lastname: Lee
authors.affiliation: Department of Biochemistry & Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea.|Brain Korea 21 PLUS Project for Medical Sciences, Severance Medical Research Institute, Seoul, Republic of Korea.
authors.forename: J-H
authors.initials: JH
authors.lastname: Baek
authors.affiliation: Department of Biochemistry & Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea.|Brain Korea 21 PLUS Project for Medical Sciences, Severance Medical Research Institute, Seoul, Republic of Korea.
authors.forename: Y-H
authors.initials: YH
authors.lastname: Cho
authors.affiliation: Department of Biochemistry & Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea.|Brain Korea 21 PLUS Project for Medical Sciences, Severance Medical Research Institute, Seoul, Republic of Korea.
authors.forename: H G
authors.initials: HG
authors.lastname: Kang
authors.affiliation: Department of Pathology, Dong-A University Medical School, Busan, Republic of Korea.
authors.forename: J S
authors.initials: JS
authors.lastname: Jeong
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors.forename: J
authors.initials: J
authors.lastname: Song
authors.affiliation: Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: H-S
authors.initials: HS
authors.lastname: Park
authors.affiliation: Department of Biochemistry & Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea.|Brain Korea 21 PLUS Project for Medical Sciences, Severance Medical Research Institute, Seoul, Republic of Korea.
authors.forename: K-H
authors.initials: KH
authors.lastname: Chun
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D056744:Cyclin B1 / Q000378:metabolism; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C534699:CCNB1 protein, human; D056744:Cyclin B1; C497761:NOTCH1 protein, human; D009842:Oligopeptides; D051881:Receptor, Notch1; D051880:Receptors, Notch; C523462:benzyloxycarbonyl-leucyl-leucyl-norleucinal; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
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