TIGAR Promotes Tumorigenesis and Protects Tumor Cells From Oxidative and Metabolic Stresses in Gastric Cancer.

Zhenhua Liu,Huamin Qin,Xuelu Li,Yue Wu,Chengjuan Xing,Zuowei Zhao,Shanni Zhang,Hongbo Zhao,Yingqiu Zhang,Menglang Yuan,Jiyue Gao

doi:10.3389/fonc.2019.01258

Abstract

Cancer cells adopt glycolysis to facilitate the generation of biosynthetic substrates demanded by cell proliferation and growth, and to adapt to stress conditions such as excessive reactive oxygen species (ROS) accumulation. TIGAR (TP53-induced glycolysis and apoptosis regulator) is a fructose-2,6-bisphosphatase that is regulated by p53. TIGAR functions to inhibit glycolysis and promote antioxidative activities, which assists the generation of NADPH to maintain the levels of GSH and thus reduces intracellular ROS. However, the functions of TIGAR in gastric cancer (GC) remain unclear. TIGAR expression levels were detected by immunoblotting and immunohistochemistry in gastric cancer samples, along with four established cell lines of GC. The functions of TIGAR were determined by utilizing shRNA-mediated knockdown experiments. The NADPH/NADP+ ratio, ROS, mitochondrial ATP production, and phosphorus oxygen ratios were determined in TIGAR-depleted cells. Xenograft experiment was conducted with BALB/c nude mice. TIGAR was up-regulated compared with corresponding non-cancerous tissues in primary GCs. TIGAR knockdown significantly reduced cell proliferation and increased apoptosis. TIGAR protected cancer cells from oxidative stress-caused damages, but also glycolysis defects. TIGAR also increased the production of NADPH in gastric cancer cells. TIGAR knockdown led to increased ROS production, elevated mitochondrial ATP production, and phosphorus oxygen ratios. The prognosis of high TIGAR expression patients was significantly poorer than those with low TIGAR expression. Taken together, TIGAR exhibits oncogenic features in GC, which can be evaluated as a target for intervention in the treatment of GC.

Highlights

Unlike normal-behaving cells, that depend on oxidative phosphorylation processes in the mitochondria to produce essential energy for cellular physiology, malignant cells shift their metabolism toward glycolysis, albeit under conditions with adequate oxygen, to facilitate the generation of biosynthetic substrates demanded by cell metabolism, and to cope with stressTIGAR Is an Oncogene in Gastric Cancer conditions like ROS [reactive oxygen species (ROS)] accumulation
These results indicate that TIGAR may play an oncogenic role in gastric cancer (GC) tumorigenesis
We found that TIGAR was highly expressed in primary gastric cancers, which is consistent with previous findings of TIGAR expressions in several types of human cancers [12,13,14,15, 23]

Summary

Introduction

TIGAR Is an Oncogene in Gastric Cancer conditions like ROS [reactive oxygen species (ROS)] accumulation. These strategies employed by cancer cells are termed “the Warburg effect” [1]. TIGAR inhibits glycolysis and transfers metabolic intermediates to alternative pentose phosphate pathway, which functions to generate ribose−5-phosphate for nucleotide synthesis and to yield NADPH to maintain the levels of glutathione (GSH) and lower intracellular ROS [5, 9, 10]. TIGAR protects cells against damages by influencing glycolysis and regulating the intracellular GSH and ROS levels, leading to suppressions in both apoptosis and autophagy while contributing to cell growth and proliferation [9, 11]

Methods

Results

Conclusion