Toll-Like Receptor-4 Is a Mediator of Proliferation in Esophageal Adenocarcinoma.

BACKGROUND: Chronic inflammation from reflux disease has been implicated as part of the development of esophageal adenocarcinoma. Toll-like receptors (TLRs), a component of the innate immune system, have been implicated in mediating hyperplasia and metaplasia in response to inflammatory stimuli. Increased TLR4 in human esophageal cancer has been correlated with its carcinogenesis. We hypothesized that TLR4 mediates proliferation of human esophageal adenocarcinoma cells. METHODS: Normal human esophageal (HET1A) and adenocarcinoma (OE33, FLO-1) cell lines were cultured using standard techniques. TLR4 was measured at baseline and in response to reflux stimuli. All cell lines were treated with the TLR4 agonist lipopolysaccharide for 48 hours, and growth response was measured. Changes in myeloid differentiation primary response 88 (MyD88), tumor necrosis factor receptor associated factor 6 (TRAF6), and nuclear factor-κB (NF-κB) activity were measured during lipopolysaccharide treatment. All cell lines had NF-κB inhibited, and growth rate response was measured. RESULTS: TLR4 was expressed in all cell lines, with increased baseline expression in adenocarcinoma cell lines (p < 0.05). Reflux stimuli increased TLR4 expression (p < 0.01) in normal esophageal cells. After treatment with lipopolysaccharide, all cell lines showed significant increases in proliferation (p < 0.05) due to the NF-κB pathway, and their growth rate was reduced with NF-κB inhibition (p < 0.05). CONCLUSIONS: TLR4 is consistently detectable in esophageal cell lines and most highly expressed in adenocarcinoma. TLR4 expression increases in an inflammatory model of reflux disease. TLR4 activation results in increased proliferation due to the TLR4-MyD88-TRAF6-NF-κB signaling pathway, and inhibition of NF-κB leads to decreased esophageal cell growth. These findings suggest TLR4 may be a target to suppress esophageal cancer growth.

Group IIa sPLA2 inhibition attenuates NF-κB activity and promotes apoptosis of lung cancer cells.

BACKGROUND/AIM: Group IIa secretory phospholipase A2 (sPLA2 IIa) has been implicated in the regulation of metastasis of non-small cell lung cancer (NSCLC) and the present study investigates its contribution to lung cancer growth and progression. PLA2s initiate signaling in several pathways that mediate cell survival including phosphatidylinositol 3-kinase-AKT (PI3K-AKT), p38 mitogen-activated protein kinase (p38 MAPK), extracellular-signal-regulated kinase (ERK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). MATERIALS AND METHODS: Human NSCLC cell lines (A549 and NCI-H358) were treated with a specific sPLA2 IIa inhibitor. Cells were assayed for apoptosis, viability, proliferation and changes in cell morphology. Effects on AKT, p38 MAPK, ERK1/2 and NF-κB signaling pathways were investigated. RESULTS: sPLA2 IIa inhibition reduced proliferation and increased apoptosis. NF-κB activity was attenuated, whereas AKT, ERK1/2, p38 MAPK were variably affected by sPLA2 IIa inhibition. NF-κB inhibitor-associated apoptosis confirmed the dominant role of NF-κB. CONCLUSION: sPLA2 IIa attenuates growth and promotes apoptosis predominantly via its effects on NF-κB activity.