Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) regulates the cell metabolism of pancreatic neuroendocrine tumors (pNET) and de-sensitizes pNET to mTOR inhibitors
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Pei-Yi Chu1,2,3,*, Shih Sheng Jiang1,*, Yan-Shen Shan4,5,*, Wen-Chun Hung1, Ming-Huang Chen6, Hui-You Lin1, Yu-Lin Chen1, Hui-Jen Tsai1,7,8 and Li-Tzong Chen1,7,8,9
1National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
2Department of Pathology, Show Chwan Memorial Hospital, Changhua, Taiwan
3School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
4Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan
5Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan
6Department of Medicine, Taipei Veterans General Hospital, School of Medicine, National Yang-Ming University, Taipei, Taiwan
7Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
8Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
9Institute of Molecular Medicine, National Cheng Kung University, Tainan, Taiwan
*These authors have contributed equally to this work
Hui-Jen Tsai, email: [email protected]
Keywords: pancreatic neuroendocrine tumor, PEPCK-M, mTOR, glycolysis, mitochondrial OXPHOS
Received: December 08, 2016 Accepted: September 13, 2017 Published: October 09, 2017
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.
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