國家衛生研究院 NHRI:Item 3990099045/10965
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    题名: Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) regulates the cell metabolism of pancreatic neuroendocrine tumors (pNET) and de-sensitizes pNET to mTOR inhibitors
    作者: Chu, PY;Jiang, SS;Shan, YS;Hung, WC;Chen, MH;Lin, HY;Chen, YL;Tsai, HJ;Chen, LT
    贡献者: National Institute of Cancer Research
    摘要: mTOR pathway activation and hypervascularity have been identified as important characteristics of pancreatic neuroendocrine tumors (pNETs). Agents targeting angiogenesis and mTOR, such as sunitinib and everolimus (RAD001), have been shown to result in progression-free survival of approximately 11 months in patients with advanced pNETs. Novel treatment is needed to extend survival. Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M), which is encoded by PCK2, catalyzes the conversion of oxaloacetate to phosphoenolpyruvate. PEPCK-M has been demonstrated to potentiate cytoplasmic phosphoenolpyruvate carboxykinase (PEPCK-C)-mediated gluconeogenesis and to play a critical role in the survival program initiated upon stress during metabolism in cancer cells. Elevated expression of PCK2 has been found in various tumors according to the results of The Cancer Genome Atlas project. However, the role of PEPCK-M aberration in cancers is not well understood. In the current study, we observed that 12 of 21 (57%) pNET patients had high expression of PEPCK-M in the tumors, whereas the normal islet cells had weak expression of PEPCK-M. Knockdown of PCK2 inhibited the proliferation of pNET cells and enhanced the sensitivity of pNET cells to mTOR inhibitors. Knockdown of PCK2 promoted glycolysis but reduced mitochondrial oxidative phosphorylation in pNET cells. The combination of mTOR inhibitors and an anti-glycolysis agent, 2-DG, synergistically or additively inhibited the proliferation of pNET cells, particularly for the cells with high expression of PEPCK-M. Therefore, targeting PEPCK-M or glycolysis combined with inhibiting mTOR is a potential therapeutic approach for the treatment of pNETs.
    日期: 2017-10-09
    關聯: Oncotarget. 2017 Oct 09;8(61):103613-103625.
    Link to: http://dx.doi.org/10.18632/oncotarget.21665
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000419562500071
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85035357034
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