Abstract 1167: Inhibition of WNT/ß-catenin signaling-related glutamine metabolism but not the Warburg effect in denervation-induced suppression of gastric tumorigenesis

Abstract

Abstract Background/aim: Cholinergic nerves have been shown to regulate gastric WNT/ß-catenin signaling in leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5)-positive stem cells and have recently been implicated in gastric tumorigenesis. Denervation by local vagotomy or botulinum neurotoxin type A injection or the muscarinic acetylcholine receptor 3 antagonist limit gastric cancer growth. The aim of this study was to further unravel the metabolic pathways underlying the vagotomy-induced suppression of gastric tumorigenesis. Methods: Unilateral subdiaphragmatic truncal vagotomy (VT) was performed in wild-type (WT) and the INS-GAS mice, a genetic mouse model of spontaneous gastric cancer. Metabolic profiling and gene expression profiling in gastric tissues at 6 months post-surgery were performed using liquid chromatography/mass spectrometry, gas chromatography/mass spectrometry, high resolution magic angle spinning NMR spectroscopy, and microarray gene expression (Illumina). Results: VT-induced suppression of tumorigenesis was manifested by reduced proliferation rate and increased apoptotic and autophagic signaling pathways, leading to reduced tumor size and prolonged survival. Principal component analysis showed four distinct clusters among 343 metabolic compounds: WT without VT, INS-GAS without VT, WT with VT and INS-GAS with VT. In the gastric tumor, the metabolic pathways that regulate stem cell homeostasis were downregulated after VT. Glutaminolytic pathway, including glutamine, glutamate, glycine and glutathione-S-S-glutathione, was down-regulated. The tricarboxylic acid cycle (TCA), including citrate, cis-aconitate, acetyle-CoA, threonine and glycine, was also down-regulated. However, glycolytic pathway, including glucose, glucose 6-phosphate, fructose 6-phosphate and lactate, was not significantly down-regulated. Signaling pathways that regulate glutamine metabolism, such as WNT/ß-catenin signaling, WNT target genes Cyclin D1, Axin2, Myc, Lgr5 and Cd44, p53 signaling, and mTOR signaling were down-regulated. The central carbon metabolism in cancer (“The Warburg effect” signaling) and lactate production were unchanged after VT. In addition, the choline metabolism, the lipid-derived eicosanoids and prostaglandins were reduced after VT. Conclusions: The denervation-induced suppression of gastric tumorigenesis was associated with the inhibition of WNT/ß-catenin signaling-related glutamine metabolism but not the Warburg effect. We suggest that glutamine and choline phospholipid metabolisms can be used for metabolism-based tumor detection with MRS and/or positron emission tomography (PET) for gastric cancer diagnosis and that blocking these metabolic functions can be a therapeutic approach for gastric cancer treatment. Citation Format: Gøran Andersen, Riyas Vettukattil, Yoku Hayakawa, Jon Erik Grønbech, Timothy C. Wang, Duan Chen, Chun Mei Zhao. Inhibition of WNT/ß-catenin signaling-related glutamine metabolism but not the Warburg effect in denervation-induced suppression of gastric tumorigenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1167. doi:10.1158/1538-7445.AM2015-1167