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Activated mTOR/P70S6K signaling pathway is involved in insulinoma tumorigenesis

Authors

  • Han-Xiang Zhan MD,

    1. Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R. China
    2. Department of General Surgery, Qilu Hospital, Shandong University, Jinan, P.R. China
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  • Lin Cong MD,

    1. Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R. China
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  • Yu-Pei Zhao MD,

    Corresponding author
    1. Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R. China
    • Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, No. 1, Shuai-fu-yuan, Dong Cheng District, Beijing 100730, P.R. China. Fax: +86-1065296014.===

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  • Tai-Ping Zhang MD,

    1. Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R. China
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  • Ge Chen MD,

    1. Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R. China
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  • Li Zhou MD,

    1. Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R. China
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  • Jun-Chao Guo MD

    1. Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R. China
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  • Han-Xiang Zhan and Lin Cong contributed equally to this work.

Abstract

Background

Insulinoma was a rare tumor and its pathogenesis was poorly understood. There had no study that focused on the role of mTOR signaling pathway in insulinoma tumorigenesis.

Materials and Methods

Expression of p-mTOR and its downstream p-P70S6K in insulinoma and normal pancreatic tissue was evaluated by immunohistochemical staining and Western blotting. In vitro study, an insulinoma cell line (INS-1) was treated with inhibitors of mTOR (rapamycin) or dual PI3K/mTOR inhibitor (NVP-BEZ235), RT-PCR, and Western blotting were applied to evaluate their influence on the expression of mTOR and P70S6K. Cell proliferation was evaluated by MTT test, cell cycle and apoptosis were analyzed by flow cytometry, insulin secretion level was evaluated by GSIS method.

Results

Positive expression of p-mTOR and p-P70S6K was much higher in insulinoma tumor specimens than the normal pancreatic islet (P < 0.05). mTOR inhibitors can induce decreased expression of mTOR and P70S6K, which resulting in inhibiting INS-1 cell proliferation, insulin secretion and inducing apoptosis. NVP-BEZ235 had better influence on inhibiting the cell proliferation and inducing apoptosis than rapamycin.

Conclusion

mTOR/P70S6K signaling pathway is involved in tumorigenesis of insulinoma, NVP-BEZ235 and rapamycin offer a promising role as novel drugs in treatment of insulinoma. J. Surg. Oncol. 2012; 106: 972–980. © 2012 Wiley Periodicals, Inc.

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