Decreased fructose-1,6-bisphosphatase-2 expression promotes glycolysis and growth in gastric cancer cells

He Li,Wenmei Li,Yuanming Pan,Rui Xing,Youyong Lu,Jiantao Cui,Huiyu Xu,Juan Wang,Hongbing Zhang

doi:10.1186/1476-4598-12-110

Abstract

BackgroundIncreasing evidence suggests that cancer is a metabolic disease. Here, we investigated the potential role of fructose-1,6-bisphosphatase-2 (FBP2), the enzyme that catalyses the hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate and inorganic phosphate in glucose metabolism, in gastric cancer (GC) development.ResultsOur data indicated that FBP2 was downregulated in GC tissues (86.2%, 100/116), and absent or low FBP2 expression in GC tissues was correlated with poor survival of GC patients (P = 0.019). Conversely, ectopic expression of FBP2 in GC cells activated AMP-activated protein kinase (AMPK) signalling, inhibited the Akt-mTOR pathway, suppressed glucose metabolism, enhanced apoptosis, and reduced cell proliferation. Bisulphite genomic sequencing (BGS) in gastric cancer cell lines revealed that the FBP2 promoter region was densely methylated, and treatment of GC cells with the demethylation reagent, 5-aza-2-deoxycytidine (5-Aza), led to an increase in FBP2 expression. Importantly, forced expression of FBP2 abrogated tumour formation of these GC cells in nude mice.ConclusionOur results indicate that FBP2 does negatively regulate cell growth, and reduced expression of FBP2 may contribute to carcinogenesis for GC. These findings suggest that restoration of FBP2 expression can be a promising strategy for the target therapy of GC.

Highlights

Increasing evidence suggests that cancer is a metabolic disease
We have shown that reduced FBP2 expression was associated with poor clinical outcome in gastric cancer (GC) patients, while FBP2 upregulation led to inhibition of glucose metabolism, cell proliferation and tumourigenicity
Decreased FBP2 expression in primary tumours is correlated with poor prognosis of GC patients In our previous study, we used significance analysis of microarrays (SAM) and Bayesian analysis of gene expression levels (BAGEL) to analyse our raw microarray data to identify genes with altered expression in gastric cancer [15]

Summary

Introduction

We investigated the potential role of fructose-1,6-bisphosphatase-2 (FBP2), the enzyme that catalyses the hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate and inorganic phosphate in glucose metabolism, in gastric cancer (GC) development. Increasing evidence in recent years indicates that cancer is a metabolic disease [5], in which cells have lost their normal checks on cell proliferation, resulting in Fructose-1,6-bisphosphatase (FBP) is one of the key enzymes in glucose metabolism. This enzyme catalyses the hydrolysis of fructose-1,6-bisphosphate to fructose6-phosphate and inorganic phosphate and exists as two isoenzymes in mammals: FBP1 and FBP2. Our findings suggested that FBP2 could be a promising biomarker for predicting the prognosis of GC patients and might provide a potential target for GC therapy

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Results

Discussion

Conclusion