Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) regulates the cell metabolism of pancreatic neuroendocrine tumors (pNET) and de-sensitizes pNET to mTOR inhibitors

Abstract

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.

PCK2 opposes mitochondrial respiration and maintains the redox balance in starved lung cancer cells

“…The enzyme exists in two different isoforms, the cytoplasmic isoform PCK1 (PEPCK-C), and the mitochondrial isoform PCK2 (PEPCK-M). Contrary to the previously assumed restriction to classic gluconeogenic tissues, PCK2 is also expressed in a variety of cancers, including lung cancer, breast cancer and prostate cancer (Chaika et al , 2012; Chen et al , 2007; Chu et al , 2017; Chun et al , 2010; Leithner et al , 2015; Leithner et al , 2018; Mendez-Lucas et al , 2014; Vincent et al , 2015; Zhao et al , 2017). However, PCK2 is also expressed in non-neoplastic tissues, including the lung (Smolle et al , 2020; Stark & Kibbey, 2014).…”

“…The copyright holder for this preprint this version posted November 24, 2020. ; https://doi.org/10.1101/2020.11.23.393686 doi: bioRxiv preprint cancer, breast cancer and prostate cancer (Chaika et al, 2012;Chen et al, 2007;Chu et al, 2017;Chun et al, 2010;Leithner et al, 2015;Leithner et al, 2018;Mendez-Lucas et al, 2014;Vincent et al, 2015;Zhao et al, 2017). However, PCK2 is also expressed in non-neoplastic tissues, including the lung (Smolle et al, 2020;Stark & Kibbey, 2014).…”

Gluconeogenesis in cancer cells – Repurposing of a starvation-induced metabolic pathway?

“…Increased expression of PCK2 in neuroendocrine tumors of the pancreas compared to non-neoplastic islet cells and a proliferation promoting effect of PCK2 were found in pancreatic neuroendocrine cancer cells associated with increased expression of tRNA processing genes [52]. In prostate cancer, a higher expression level of PCK2 has been reported in metastases compared to primary tumors or normal prostate [53].…”

“…Increased in colon carcinoma [39], lung cancer (NSCLC) [41], and neuroendocrine tumors of the pancreas [52]…”

Flexibility and Adaptation of Cancer Cells in a Heterogenous Metabolic Microenvironment

“…Silencing or inhibition of the pathway impaired lung cancer cell survival under glucose deprivation and 3D cancer spheroid growth. Subsequently, PCK2 or PCK1 have been found to be active especially under conditions of glucose deprivation to promote cell survival or proliferation in diverse cancer types [ 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 ]. Inhibition of cancer growth by inhibition of PCK1 or PCK2 has been shown in different tumor models in vivo, including xenografts of lung cancer, prostate cancer and colon cancer [ 71 , 73 , 74 , 77 , 78 , 81 ].…”