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

Oncogene volume 35, pages 251–260 (2016)Cite this article

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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.

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Acknowledgements

The authors are grateful to the FACS facility staff of the National Cancer Center (NCC) in Korea for their technical support. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. NRF-2014R1A2A1A11050600), and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2014R1A1A2055009).

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Authors and Affiliations

  1. Department of Biochemistry & Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea

    S-J Kim, H-W Lee, J-H Baek, Y-H Cho, H G Kang & K-H Chun

  2. Brain Korea 21 PLUS Project for Medical Sciences, Severance Medical Research Institute, Seoul, Republic of Korea

    S-J Kim, J-H Baek, Y-H Cho, H G Kang & K-H Chun

  3. Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea

    H-W Lee & J Song

  4. Department of Pathology, Dong-A University Medical School, Busan, Republic of Korea

    J S Jeong

  5. Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea

    H-S Park

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Kim, SJ., Lee, HW., Baek, JH. et al. Activation of nuclear PTEN by inhibition of Notch signaling induces G2/M cell cycle arrest in gastric cancer. Oncogene 35, 251–260 (2016). https://doi.org/10.1038/onc.2015.80

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