TLR4-mediated galectin-1 production triggers epithelial-mesenchymal transition in colon cancer cells through ADAM10- and ADAM17-associated lactate production

Mol Cell Biochem. 2017 Jan;425(1-2):191-202. doi: 10.1007/s11010-016-2873-0. Epub 2016 Nov 12.

Abstract

Toll-like receptor 4 (TLR4) activation is a key contributor to the carcinogenesis of colon cancer. Overexpression of galectin-1 (Gal-1) also correlates with increased invasive activity of colorectal cancer. Lactate production is a critical predictive factor of risk of metastasis, but the functional relationship between intracellular lactate and Gal-1 expression in TLR4-activated colon cancer remains unknown. In this study, we investigated the underlying mechanism and role of Gal-1 in metastasis and invasion of colorectal cancer (CRC) cells after TLR4 stimulation. Exposure to the TLR4 ligand lipopolysaccharide (LPS) increased expression of Gal-1, induced EMT-related cytokines, triggered the activation of glycolysis-related enzymes, and promoted lactate production. Gene silencing of TLR4 and Gal-1 in CRC cells inhibited lactate-mediated epithelial-mesenchymal transition (EMT) after TLR4 stimulation. Gal-1-mediated activation of a disintegrin and metalloproteinase 10 (ADAM10) and ADAM 17 increased the invasion activity and expression of mesenchymal characteristics in LPS-activated CRC cells. Conversely, inhibition of ADAM10 or ADAM17 effectively blocked the generation of lactate and the migration capacity of LPS-treated CRC cells. Thus, the TLR4/Gal-1 signaling pathway regulates lactate-mediated EMT processes through the activation of ADAM10 and ADAM17 in CRC cells.

Keywords: A disintegrin and metalloproteinase; Colorectal cancer; Epithelial-mesenchymal transition; Galectin-1; Toll-like receptor 4.

MeSH terms

  • ADAM10 Protein / genetics
  • ADAM10 Protein / metabolism*
  • ADAM17 Protein / genetics
  • ADAM17 Protein / metabolism*
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism*
  • Cell Line, Tumor
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism*
  • Epithelial-Mesenchymal Transition*
  • Galectin 1 / genetics
  • Galectin 1 / metabolism*
  • Humans
  • Lactic Acid / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Signal Transduction*
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism*

Substances

  • Galectin 1
  • LGALS1 protein, human
  • Membrane Proteins
  • Neoplasm Proteins
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Lactic Acid
  • Amyloid Precursor Protein Secretases
  • ADAM10 Protein
  • ADAM10 protein, human
  • ADAM17 Protein
  • ADAM17 protein, human