Paraoxonase 2 Facilitates Pancreatic Cancer Growth and Metastasis by Stimulating GLUT1-Mediated Glucose Transport

Mol Cell. 2017 Aug 17;67(4):685-701.e6. doi: 10.1016/j.molcel.2017.07.014. Epub 2017 Aug 10.

Abstract

Metabolic deregulation is a hallmark of human cancers, and the glycolytic and glutamine metabolism pathways were shown to be deregulated in pancreatic ductal adenocarcinoma (PDAC). To identify new metabolic regulators of PDAC tumor growth and metastasis, we systematically knocked down metabolic genes that were overexpressed in human PDAC tumor samples using short hairpin RNAs. We found that p53 transcriptionally represses paraoxonase 2 (PON2), which regulates GLUT1-mediated glucose transport via stomatin. The loss of PON2 initiates the cellular starvation response and activates AMP-activated protein kinase (AMPK). In turn, AMPK activates FOXO3A and its transcriptional target, PUMA, which induces anoikis to suppress PDAC tumor growth and metastasis. Pharmacological or genetic activation of AMPK, similar to PON2 inhibition, blocks PDAC tumor growth. Collectively, our results identify PON2 as a new modulator of glucose transport that regulates a pharmacologically tractable pathway necessary for PDAC tumor growth and metastasis.

Keywords: GLUT1; PON2; anoikis; glucose; metabolism; pancreatic cancer.

MeSH terms

  • AMP-Activated Protein Kinases / analysis
  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Aryldialkylphosphatase / genetics
  • Aryldialkylphosphatase / metabolism*
  • Carcinoma, Pancreatic Ductal / drug therapy
  • Carcinoma, Pancreatic Ductal / enzymology*
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Cell Movement* / drug effects
  • Cell Proliferation* / drug effects
  • Energy Metabolism* / drug effects
  • Female
  • Forkhead Box Protein O3 / genetics
  • Forkhead Box Protein O3 / metabolism
  • Gene Expression Regulation, Neoplastic
  • Glucose / metabolism
  • Glucose Transporter Type 1 / genetics
  • Glucose Transporter Type 1 / metabolism*
  • Humans
  • Liver Neoplasms / enzymology*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / prevention & control
  • Liver Neoplasms / secondary
  • Lung Neoplasms / enzymology*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / prevention & control
  • Lung Neoplasms / secondary
  • Male
  • Mice, Nude
  • Mutation
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / enzymology*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins p21(ras) / genetics
  • RNA Interference
  • Signal Transduction
  • Time Factors
  • Transcription, Genetic
  • Transfection
  • Tumor Burden
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • BBC3 protein, human
  • FOXO3 protein, human
  • Forkhead Box Protein O3
  • Glucose Transporter Type 1
  • KRAS protein, human
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • SLC2A1 protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • AMP-Activated Protein Kinases
  • Aryldialkylphosphatase
  • PON2 protein, human
  • Proto-Oncogene Proteins p21(ras)
  • Glucose