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Specific inhibition of mTOR pathway induces anti-proliferative effect and decreases the hormone secretion in cultured pituitary adenoma cells

  • Laboratory Investigation
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Abstract

There are some evidences that pituitary tumors may be sensitive to the anti-proliferative effects of mammalian target of rapamycin (mTOR) inhibitors, while the mechanism and effects remains unclear, it is necessary to find if a specific mTOR inhibition, including the blocking of both mTOR function and expression, generate any effects on pituitary adenoma cells. The object of this study was to examine if specific inhibition of mTOR induced anti-proliferative effect and decreased the GH and PRL hormones secretion in GH3 and MtT/E pituitary adenoma cells by using a kind of mTOR shRNA lentiviral vector. The in vitro experiments results showed mTOR shRNA transfection robustly reduced the GH3 and MtT/E cells viability in all durations (1–6 days) we performed, also specifically decreased both GH and PRL hormones external secretion in GH3 cells. Further results suggested that specific inhibition of mTOR decreased the hormones secretion through anti-proliferation effects on GH3 cells and reducing the hormones synthesis, but not through affecting the process of hormones secretion. Then we used phosphatidic acid (PA), a kind of mTOR activator, to promote the cell proliferation and GH and PRL hormones secretion in GH3 cells while the effects were blocked by mTOR shRNA transfection. In addition, we examined in vitro effects of PA treatment and mTOR shRNA gene transfection on major proteins expressed in the mTOR pathway in GH3 cells, and confirmed that PA treatment significant increased the protein levels of pmTOR, pS6 K and p4EBP1 in the scramble shRNA group, while the increase of protein levels was blocked by mTOR shRNA gene transfection. Moreover, mTOR shRNA gene transfection definitely inhibited the expression of mTOR and reduced the expression of pmTOR, pS6K and p4EBP1 in either PA or no PA treatment groups. These findings indicated that specific inhibition of mTOR pathway induced anti-proliferative effect and decreased the GH and PRL hormones secretion in cultured pituitary adenoma cells, which may be a novel promising and potential treatment modality for patients with secreting or non-secreting pituitary adenomas.

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Acknowledgments

The authors would gratefully acknowledge the support from China Pituitary Adenoma Specialist Council (CPASC).

Funding

This study was fully supported by below grants: National High Technology Research and Development Program of China (2014AA020611, Y.Z.), National Program for Support of Top-Notch Young Professionals (Y.Z.), National Natural Science Foundation of China (81172391, Y.Z.), Program for New Century Excellent Talents in University (NCET-10-0356, Y.Z.), Shanghai Rising-Star Tracking Program (12QH1400400, Y.Z.), National Natural Science Foundation of China (81200890, R.X.), Scientific Research Foundation of Shanghai Municipal Commission of Health and Family Planning (20134238, R.X.)

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    Authors and Affiliations

    1. Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, 200040, China

      Rong Xie, Wen-Qiang He, Ming Shen, Xue-Fei Shou, Yong-Fei Wang, Wei-Min Bao & Yao Zhao

    2. Shanghai Medical College, Fudan University, Shanghai, 200040, China

      Rong Xie, Wen-Qiang He, Ming Shen, Xue-Fei Shou, Yong-Fei Wang, Wei-Min Bao & Yao Zhao

    3. Shanghai Pituitary Tumor Center, Shanghai, 200040, China

      Rong Xie, Wen-Qiang He, Ming Shen, Xue-Fei Shou, Yong-Fei Wang, Wei-Min Bao & Yao Zhao

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    1. Rong Xie
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    Correspondence to Wei-Min Bao or Yao Zhao.

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    Rong Xie and Wen-Qiang He have contributed equally to this article and should be considered as co-first authors.

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    Xie, R., He, WQ., Shen, M. et al. Specific inhibition of mTOR pathway induces anti-proliferative effect and decreases the hormone secretion in cultured pituitary adenoma cells. J Neurooncol 125, 79–89 (2015). https://doi.org/10.1007/s11060-015-1895-x

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    • DOI: https://doi.org/10.1007/s11060-015-1895-x

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