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

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.

Toll-like receptor 2 stimulation promotes colorectal cancer cell growth via PI3K/Akt and NF-κB signaling pathways.

Toll-like receptor (TLR) 2 is a key regulator of innate immune responses and has been shown to play an important role in inflammation-associated cancers. In this study, we aimed to evaluate the role of TLR2 in colorectal cancer (CRC). We demonstrated that TLR2 mRNA and protein expression was significantly upregulated in tumors from CRC patients and indicated poor prognosis. Using the TLR2 agonist Pam3Cys (P3C) to activate TLR2 signaling in human CRC cell lines, we showed that TLR2 drives cellular proliferation, which was dependent upon PI3K/Akt and NF-κB signaling pathways and was associated with the upregulation of anti-apoptotic genes BCL2A1, WISP1 and BIRC3. Likewise, pharmacological blockade of PI3K/Akt and NF-κB pathways mitigated the CRC pro-survival effects of TLR2 stimulation. Furthermore, genetic ablation of TLR2 using CRISPR/Cas9 suppressed CRC cell proliferation, invasion and migration. Taken together, these findings demonstrate that TLR2 plays an important role in colorectal tumorigenesis and may represent a promising therapeutic target in CRC.