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

• Published in: Oncogene Vol. 35; no. 2; pp. 251 - 260
• Main Authors: Kim, S-J, Lee, H-W, Baek, J-H, Cho, Y-H, Kang, H G, Jeong, J S, Song, J, Park, H-S, Chun, K-H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.01.2016; Nature Publishing Group
• Subjects: 13/1; 13/105; 13/109; 13/2; 13/31; 13/89; 13/95; 14; 631/67/1504/1829; 64/60; Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Cancer therapies; Cell Biology; Cell cycle; Cell Line, Tumor; Cell Nucleus - metabolism; Cellular signal transduction; Chemotherapy; Cyclin B1; Cyclin B1 - metabolism; Dephosphorylation; Development and progression; Female; G2 Phase Cell Cycle Checkpoints - drug effects; Gastric cancer; Gene Expression Regulation, Neoplastic; Gene mutations; Genetic aspects; Health aspects; Human Genetics; Humans; Internal Medicine; Kinases; Localization; Medicine; Medicine & Public Health; Mice, Inbred BALB C; Mutation; Notch1 protein; Oligopeptides - pharmacology; Oncology; original-article; Phosphorylation; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; PTEN protein; Receptor, Notch1 - genetics; Receptor, Notch1 - metabolism; Receptors, Notch - genetics; Receptors, Notch - metabolism; Secretase; Signal Transduction; siRNA; Stomach cancer; Stomach Neoplasms - drug therapy; Stomach Neoplasms - metabolism; Stomach Neoplasms - mortality; Stomach Neoplasms - pathology; Toxicity; Tumor suppressor genes; Tumorigenesis; Tumors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.80

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.