Pancreatic neuroendocrine tumor (pNET) is a rare type of pancreatic cancer. Agents targeting angiogenesis and mTOR, sunitinib and everolimus, have been shown to prolong the progression free survival by around 11 months for pNET patients. To further improve the survival of pNET, a novel treatment is needed. Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M), which is encoded by PCK2, was demonstrated to play a critical role in the survival program initiated upon stress in cancer metabolism. Although elevated expression of PCK2 has been found in various tumors, the role of PEPCK-M aberration in cancers is not well understood. In our study, 12 of 21 pNET patients had high expression of PEPCK-M in the tumors. 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 of pNET cells. Combination of mTOR inhibitors and anti-glycolysis agent synergistically inhibited the proliferation of pNET cells. Therefore targeting PEPCK-M or glycolysis combined with mTOR inhibitors is a potential therapeutic approach for the treatment of pNET.
