Toll-like receptor 2 regulates metabolic reprogramming in gastric cancer via superoxide dismutase 2.

Abstract

Toll-like receptors (TLRs) play critical roles in host defense after recognition of conserved microbial- and host-derived components, and their dysregulation is a common feature of various inflammation-associated cancers, including gastric cancer (GC). Despite the recent recognition that metabolic reprogramming is a hallmark of cancer, the molecular effectors of altered metabolism during tumorigenesis remain unclear. Here, using bioenergetics function assays on human GC cells, we reveal that ligand-induced activation of TLR2, predominantly through TLR1/2 heterodimer, augments both oxidative phosphorylation (OXPHOS) and glycolysis, with a bias toward glycolytic activity. Notably, DNA microarray-based expression profiling of human cancer cells stimulated with TLR2 ligands demonstrated significant enrichment of gene-sets for oncogenic pathways previously implicated in metabolic regulation, including reactive oxygen species (ROS), p53 and Myc. Moreover, the redox gene encoding the manganese-dependent mitochondrial enzyme, superoxide dismutase (SOD)2, was strongly induced at the mRNA and protein levels by multiple signaling pathways downstream of TLR2, namely JAK-STAT3, JNK MAPK and NF-κB. Furthermore, siRNA-mediated suppression of SOD2 ameliorated the TLR2-induced metabolic shift in human GC cancer cells. Importantly, patient-derived tissue microarrays and bioinformatics interrogation of clinical datasets indicated that upregulated expression of TLR2 and SOD2 were significantly correlated in human GC, and the TLR2-SOD2 axis was associated with multiple clinical parameters of advanced stage disease, including distant metastasis, microvascular invasion and stage, as well as poor survival. Collectively, our findings reveal a novel TLR2-SOD2 axis as a potential biomarker for therapy and prognosis in cancer.

• Authors: You Dong Liu, Liang Yu, Le Ying, Jesse Balic, Hugh Gao, Nian Tao Deng, Alison West, Feng Yan, Cheng Bo Ji, Daniel Gough, Patrick Tan, Brendan J Jenkins, Ji Kun Li
• Journal: International journal of cancer (Int J Cancer) Vol. 144 Issue 12 Pg. 3056-3069 (06 15 2019) ISSN: 1097-0215 [Electronic] United States
• PMID: 30536754 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

Chemical References

• Biomarkers, Tumor
• Reactive Oxygen Species
• TLR2 protein, human
• Toll-Like Receptor 2
• Superoxide Dismutase
• superoxide dismutase 2

Topics

• Biomarkers, Tumor (metabolism)
• Cell Line, Tumor
• Cellular Reprogramming (physiology)
• Energy Metabolism
• Enzyme Induction
• Glycolysis
• Humans
• Immunohistochemistry
• Oxidative Phosphorylation
• Reactive Oxygen Species (metabolism)
• Signal Transduction
• Stomach Neoplasms (metabolism, pathology)
• Superoxide Dismutase (metabolism)
• Tissue Array Analysis
• Toll-Like Receptor 2 (metabolism)
• Up-Regulation