title: 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.
authors.affiliation: Research Support Unit, San Cecilio University Hospital, Granada, Spain; Ciber of Hepatic and Digestive Diseases (CIBERehd), Granada, Spain.
authors.forename: Josefa
authors.initials: J
authors.lastname: León
authors.forename: Jorge
authors.initials: J
authors.lastname: Casado
authors.forename: Sergio M
authors.initials: SM
authors.lastname: Jiménez Ruiz
authors.forename: María Sol
authors.initials: MS
authors.lastname: Zurita
authors.forename: Cristina
authors.initials: C
authors.lastname: González-Puga
authors.forename: Juan D
authors.initials: JD
authors.lastname: Rejón
authors.forename: Ana
authors.initials: A
authors.lastname: Gila
authors.forename: Paloma
authors.initials: P
authors.lastname: Muñoz de Rueda
authors.forename: Esther J
authors.initials: EJ
authors.lastname: Pavón
authors.forename: Russel J
authors.initials: RJ
authors.lastname: Reiter
authors.forename: Angela
authors.initials: A
authors.lastname: Ruiz-Extremera
authors.forename: Javier
authors.initials: J
authors.lastname: Salmerón
mesh_terms: D001483:Base Sequence; D018938:Caco-2 Cells; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000235:genetics; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008550:Melatonin / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics
chemical_list: D019332:Endothelin-1; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D016328:NF-kappa B; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D051057:Proto-Oncogene Proteins c-akt; D008550:Melatonin
keywords: FoxO-1; NF-κβ; colorectal cancer; endothelin-1; melatonin