Gluconeogenesis in Cancer: Function and Regulation of PEPCK, FBPase, and G6Pase

Trends Cancer. 2019 Jan;5(1):30-45. doi: 10.1016/j.trecan.2018.11.003. Epub 2018 Dec 20.

Abstract

Cancer cells display a high rate of glycolysis in the presence of oxygen to promote proliferation. Gluconeogenesis, the reverse pathway of glycolysis, can antagonize aerobic glycolysis in cancer via three key enzymes - phosphoenolpyruvate carboxykinase (PEPCK), fructose-1,6-bisphosphatase (FBPase), and glucose-6-phosphatase (G6Pase). Recent studies have revealed that, in addition to metabolic regulation, these enzymes also play a role in signaling, proliferation, and the cancer stem cell (CSC) tumor phenotype. Multifaceted regulation of PEPCK, FBPase, and G6Pase through transcription, epigenetics, post-translational modification, and enzymatic activity is observed in different cancers. We review here the function and regulation of key gluconeogenic enzymes and new therapeutic opportunities.

Keywords: FBPase; G6Pase; PEPCK; aerobic glycolysis; gluconeogenesis; targeted therapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Cell Proliferation / drug effects
  • Gene Expression Regulation, Neoplastic
  • Gluconeogenesis* / drug effects
  • Gluconeogenesis* / genetics
  • Glucose / biosynthesis*
  • Glucose-6-Phosphatase / genetics
  • Glucose-6-Phosphatase / metabolism
  • Glycolysis
  • Humans
  • Molecular Targeted Therapy
  • Neoplasms / drug therapy
  • Neoplasms / etiology
  • Neoplasms / metabolism*
  • Phosphoenolpyruvate Carboxykinase (ATP) / genetics
  • Phosphoenolpyruvate Carboxykinase (ATP) / metabolism
  • Reactive Oxygen Species / metabolism

Substances

  • Antineoplastic Agents
  • Reactive Oxygen Species
  • Glucose-6-Phosphatase
  • PCK2 protein, human
  • Phosphoenolpyruvate Carboxykinase (ATP)
  • Glucose