ME1 Regulates NADPH Homeostasis to Promote Gastric Cancer Growth and Metastasis

Cancer Res. 2018 Apr 15;78(8):1972-1985. doi: 10.1158/0008-5472.CAN-17-3155.

Abstract

Genomic alterations of tumor suppressorsoften encompass collateral protein-coding genes that create therapeutic vulnerability to further inhibition of their paralogs. Here, we report that malic enzyme 2 (ME2) is frequently hemizygously codeleted with SMAD4 in gastric cancer. Its isoenzyme ME1 was upregulated to replenish the intracellular reducing equivalent NADPH and to maintain redox homeostasis. Knockdown of ME1 significantly depleted NADPH, induced high levels of reactive oxygen species (ROS), and ultimately cell apoptosis under oxidative stress conditions, such as glucose starvation and anoikis, in ME2-underexpressed cells. Moreover, ME1 promoted tumor growth, lung metastasis, and peritoneal dissemination of gastric cancer in vivo Intratumoral injection of ME1 siRNA significantly suppressed tumor growth in cell lines and patient-derived xenograft-based models. Mechanistically, ME1 was transcriptionally upregulated by ROS in an ETV4-dependent manner. Overexpression of ME1 was associated with shorter overall and disease-free survival in gastric cancer. Altogether, our results shed light on crucial roles of ME1-mediated production of NADPH in gastric cancer growth and metastasis.Significance: These findings reveal the role of malic enzyme in growth and metastasis.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/8/1972/F1.large.jpg Cancer Res; 78(8); 1972-85. ©2018 AACR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenovirus E1A Proteins / physiology
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / physiology*
  • Cell Survival / physiology
  • Down-Regulation
  • Female
  • Glucose / metabolism
  • Heterografts
  • Homeostasis / physiology*
  • Humans
  • Lung Neoplasms / secondary*
  • Malate Dehydrogenase / genetics
  • Malate Dehydrogenase / metabolism
  • Malate Dehydrogenase / physiology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • NADP / metabolism*
  • Peritoneal Neoplasms / secondary*
  • Prognosis
  • Proto-Oncogene Proteins / physiology
  • Reactive Oxygen Species / metabolism
  • Smad4 Protein / genetics
  • Stomach Neoplasms / enzymology
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology*
  • Up-Regulation

Substances

  • Adenovirus E1A Proteins
  • ETV4 protein, human
  • Proto-Oncogene Proteins
  • Reactive Oxygen Species
  • SMAD4 protein, human
  • Smad4 Protein
  • NADP
  • Malate Dehydrogenase
  • malate dehydrogenase (decarboxylating)
  • Glucose