Malic Enzyme 1 (ME1) is pro-oncogenic in ApcMin/+ mice

Abstract

Cytosolic Malic Enzyme (ME1) provides reduced NADP for anabolism and maintenance of redox status. To examine the role of ME1 in tumor genesis of the gastrointestinal tract, we crossed mice having augmented intestinal epithelial expression of ME1 (ME1-Tg mice) with ApcMin/+ mice to obtain male ApcMin/+/ME1-Tg mice. ME1 protein levels were significantly greater within gut epithelium and adenomas of male ApcMin/+/ME1-Tg than ApcMin/+ mice. Male ApcMin/+/ME1-Tg mice had larger and greater numbers of adenomas in the small intestine (jejunum and ileum) than male ApcMin/+ mice. Male ApcMin/+/ME1-Tg mice exhibited greater small intestine crypt depth and villus length in non-adenoma regions, correspondent with increased KLF9 protein abundance in crypts and lamina propria. Small intestines of male ApcMin/+/ME1-Tg mice also had enhanced levels of Sp5 mRNA, suggesting Wnt/β-catenin pathway activation. A small molecule inhibitor of ME1 suppressed growth of human CRC cells in vitro, but had little effect on normal rat intestinal epithelial cells. Targeting of ME1 may add to the armentarium of therapies for cancers of the gastrointestinal tract.

NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications

“…ME1 and ME3 require NADP + and ME2 utilizes either NAD + or NADP + for their catalytic activities, thus NADPH can be produced by ME both directly and indirectly through the activity of the NNT that catalyzes the transfer of hydride ions from NADH to NADP + and produces NADPH in mitochondria. 90 However, ME1 and ME2 seem to be the main isoforms because ME3 is hardly negligibly detected in many assessed mammalian cells. 91 The overexpression of ME1 is significantly associated with a poor prognosis for people with cancer, including those with gastric cancer, oral squamous cell carcinoma, breast cancer, lung cancer, etc.…”

“…189 Further, ME1 treated with the inhibitor (piperazine-1-pyrrolidine-2,5-dione) has little effect on normal rat intestinal epithelial cells but strongly suppresses human CRC cell growth by targeting ME1 NADP + -binding site and reducing the NADPH level. 90 Lanthanide treatment represses cell proliferation and the epithelial-mesenchymal transition (EMT) by inhibiting ME1 in oral squamous cell carcinoma cells. 93 In addition, CPTs are also considered to be targeted.…”

Single-cell RNA-seq identifies unique transcriptional landscapes of human nucleus pulposus and annulus fibrosus cells

“…ACSS1 and LDHA are common to both glycolysis and pyruvate metabolism. ME1 plays a crucial role in pyruvate metabolism through the conversion of malate to pyruvate in the cytoplasm, while also generating NADPH in the process [30][31][32] . www.nature.com/scientificreports/ The pyruvate produced can then either enter the TCA cycle or be converted to lactate in the cells 33 .…”

Malic enzyme 1 (ME1) in the biology of cancer: it is not just intermediary metabolism

“…Remarkably, when these same mutant ME1 proteins were expressed in cells in which WT ME1 was suppressed, augmented cell growth and colony formation in vitro were found, supporting the conclusion that ME1's proproliferative effects are primarily mediated by interaction with and activation of 6PGD (Yao et al 2017) (Table 3). This new mechanism may explain some of the observed effects of KD and overexpression of ME1 in tumor cells (Table 3); however, they are not easily reconciled with the cellular growth-inhibitory effects of ME1 active siteinhibitors (Zhang et al 2006, Saha et al 2014, Fernandes et al 2018. The reciprocal and dynamic regulation of ME1 activity (manifested as increased NADPH/ NADP ratio and increased production of fatty acids) by acetylation at amino acid K337 (positive regulation) and by phosphorylation at amino acid S336 (negative regulation) (Zhu et al 2020) raises the important question of whether post-translational modification(s) of ME1 affect its interactions with 6PGD, in differing tumor types and tissue contexts.…”