Abstract

Brain-derived neurotrophic factor (BDNF) is a potent neurotrophic factor that has been shown to affect cancer cell metastasis and migration. In the present study, we investigated the mechanisms of BDNF-induced cell migration in colon cancer cells. The migratory activities of two colon cancer cell lines, HCT116 and SW480, were found to be increased in the presence of human BDNF. Heme oxygenase-1 (HO)-1 is known to be involved in the development and progression of tumors. However, the molecular mechanisms that underlie HO-1 in the regulation of colon cancer cell migration remain unclear. Expression of HO-1 protein and mRNA increased in response to BDNF stimulation. The BDNF-induced increase in cell migration was antagonized by a HO-1 inhibitor and HO-1 siRNA. Furthermore, the expression of vascular endothelial growth factor (VEGF) also increased in response to BDNF stimulation, as did VEGF mRNA expression and transcriptional activity. The increase in BDNF-induced cancer cell migration was antagonized by a VEGF-neutralizing antibody. Moreover, transfection with HO-1 siRNA effectively reduced the increased VEGF expression induced by BDNF. The BDNF-induced cell migration was regulated by the ERK, p38, and Akt signaling pathways. Furthermore, BDNF-increased HO-1 and VEGF promoter transcriptional activity were inhibited by ERK, p38, and AKT pharmacological inhibitors and dominant-negative mutants in colon cancer cells. These results indicate that BDNF increases the migration of colon cancer cells by regulating VEGF/HO-1 activation through the ERK, p38, and PI3K/Akt signaling pathways. The results of this study may provide a relevant contribution to our understanding of the molecular mechanisms by which BDNF promotes colon cancer cell motility.