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.

Melatonin treatment induces apoptosis through regulating the nuclear factor-κB and mitogen-activated protein kinase signaling pathways in human gastric cancer SGC7901 cells

“…Treatment with melatonin at a concentration of 2 mM was demonstrated to increase expression of p-p38 and p-JNK proteins. Previous immunofluorescence studies of p65-stained cells in addition to results of the present study, have suggested that 1-2 mM melatonin inhibits the translocation of NF-κB-p65 from the cytoplasm to the nucleus (28)(29)(30). These results correspond with the findings of the current study that melatonin markedly decreased cell viability and induced apoptosis in SGC7901 cells.…”

Melatonin-Induced Oncostasis, Mechanisms and Clinical Relevance

“…Melatonin suppresses the formation of ET-1 by inhibiting endothelin-converting enzyme 1 [102]. Additionally, this inhibition is associated with a reduction in edn-1 mRNA expression (the first step in ET-1 synthesis), which in turn results from the inactivation of FOXO1 and NF-B transcription factors [103].…”

The melatonin immunomodulatory actions in radiotherapy

“…Melatonin can reduce angiogenesis by the scavenging of ROS generation and inhibiting HIF-1α, sphingosine kinase 1, COX-2, and vascular endothelial growth factor (VEGF) (Park et al 2010;Wu et al 2014;Cho et al 2011). Also, melatonin reduces the effects of growth factors on tumor cells through the inhibition of insulin-like growth factor 1 (IGF-1), epidermal growth factor receptor (EGFR), and endothelin 1 (ET-1), which are strong stimulators of angiogenesis in cancer cells (Jardim-Perassi et al 2014;Cos and Blask 1994;León et al 2014). Zhou et al (2015) showed that melatonin inhibits angiogenesis in gastric cancer cells and in a tumor-bearing nude mouse model.…”