Dynamic ROS Control by TIGAR Regulates the Initiation and Progression of Pancreatic Cancer

Cancer Cell. 2020 Feb 10;37(2):168-182.e4. doi: 10.1016/j.ccell.2019.12.012. Epub 2020 Jan 23.

Abstract

The TIGAR protein has antioxidant activity that supports intestinal tissue repair and adenoma development. Using a pancreatic ductal adenocarcinoma (PDAC) model, we show that reactive oxygen species (ROS) regulation by TIGAR supports premalignant tumor initiation while restricting metastasis. Increased ROS in PDAC cells drives a phenotypic switch that increases migration, invasion, and metastatic capacity. This switch is dependent on increased activation of MAPK signaling and can be reverted by antioxidant treatment. In mouse and human, TIGAR expression is modulated during PDAC development, with higher TIGAR levels in premalignant lesions and lower TIGAR levels in metastasizing tumors. Our study indicates that temporal, dynamic control of ROS underpins full malignant progression and helps to rationalize conflicting reports of pro- and anti-tumor effects of antioxidant treatment.

Keywords: ERK; PDAC; ROS regulation; TIGAR; metastasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Proliferation / genetics
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Pancreatic Neoplasms / genetics*
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / metabolism*
  • Reactive Oxygen Species / metabolism*

Substances

  • Apoptosis Regulatory Proteins
  • Intracellular Signaling Peptides and Proteins
  • Reactive Oxygen Species
  • Phosphoric Monoester Hydrolases
  • TIGAR protein, human