Lathyrus sativus diamine oxidase counteracts histamine-induced cell proliferation, migration and pro-angiogenic mediators release in human colon adenocarcinoma cell line caco-2

Because histamine is a modulator of cancer cell proliferation and invasiveness, this study aimed at investigating the effect of Lathyrus sativus–derived diamine oxidase (LSAO) and its mechanism of action on Caco‐2 cell line, considering that LSAO catalizes the oxidative deamination of histamine to the corresponding aldehyde, NH3 and H2O2. Histamine (0.01–1 μM) caused a proliferative effect on Caco‐2 cells promoting cell migration, invasion and nitric oxide and vascular endothelial growth factor release. Histamine (1 μM) stimulus also down regulated occludin expression, favouring up regulation of pro‐proliferative nuclear protein Ki67. Incubation with LSAO (0.004–0.4 μM) resulted in a significant inhibition of histamine‐induced effects. LSAO rescued occludin expression and down regulated Ki67, and it inhibited histamine‐induced increase of both MMP‐2 and 9 expression. Histamine effects were mediated by RhoA‐GTP down regulation and inversely related to phospho‐ p38MAPK/p50/65 up regulation. These effects were counteracted by LSAO incubation. Histamine catabolism by LSAO accounts for a significant down regulation of proliferation and invasiveness of Caco‐2 cells. This study highlights the importance to control histamine levels in contrasting pro‐angiogenic and metastatization capability of colon cancer cells and expands the knowledge about the diamine oxidase from L. sativus seeding as a phytotherapeutic approach for colon cancer.