Melatonin reduces endothelin‐1 expression and secretion in colon cancer cells through the inactivation of FoxO‐1 and NF‐κβ

Abstract Melatonin is an indoleamine that is synthesised from tryptophan under the control of the enzymes arylalkylamine N‐acetyltransferase (AA‐NAT) and acetylserotonin methyltransferase (ASMT). Melatonin inhibits colon cancer growth in both in vivo and in vitro models; however, a precise mechanism responsible for inhibiting tumour growth has not been clearly described. Endothelin‐1 (ET‐1) is a peptide that acts as a survival factor in colon cancer, inducing cell proliferation, protecting carcinoma cells from apoptosis and promoting angiogenesis. The data presented show that melatonin inhibits edn‐1 mRNA expression (the first step in ET‐1 synthesis), ECE‐1 protein expression and the release of ET‐1 from colorectal cancer cells in vitro. ET‐1 levels in cultured media present a similar inhibition pattern to that of edn‐1 mRNA expression despite the inhibition of ECE‐1 protein after melatonin treatment, which suggests that an endopeptidase other than ECE‐1 could be mainly responsible for ET‐1 synthesis. The inhibition of edn‐1 expression is due to an inactivation of FoxO1 and NF‐ κβ transcription factors. FoxO1 inactivation is associated with an increased Src phosphorylation, due to elevated cAMP content and PKA activity, whereas NF‐ κβ inactivation is associated with the blockade of Akt and ERK phosphorylation due to the inhibition of PKC activity after melatonin treatment. Melatonin also inhibits edn‐1 promoter activity regulated by FoxO1 and NF‐ κβ . Finally, a significant correlation was observed between AA‐NAT and edn‐1 expression downregulation in human colorectal cancer tissues. In conclusion, melatonin may be useful in treating colon carcinoma in which the activation of ET‐1 plays a role in tumour growth and progression.