title: TLR4-mediated galectin-1 production triggers epithelial-mesenchymal transition in colon cancer cells through ADAM10- and ADAM17-associated lactate production.
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.
authors.affiliation: Department of Biochemistry, Kosin University College of Medicine, Busan, 49267, Republic of Korea.
authors.forename: Ga Bin
authors.initials: GB
authors.lastname: Park
authors.affiliation: Department of Anatomy, Inje University College of Medicine, 75 Bokji-ro, Jin-gu, Busan, 47392, Republic of Korea. kimdj@inje.ac.kr.
authors.forename: Daejin
authors.initials: D
authors.lastname: Kim
mesh_terms: D000072197:ADAM10 Protein / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D037483:Galectin 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D037483:Galectin 1; C445499:LGALS1 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D019344:Lactic Acid; D053829:Amyloid Precursor Protein Secretases; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human
keywords: A disintegrin and metalloproteinase; Colorectal cancer; Epithelial-mesenchymal transition; Galectin-1; Toll-like receptor 4