title: Melatonin exerts by an autocrine loop antiproliferative effects in cholangiocarcinoma: its synthesis is reduced favoring cholangiocarcinoma growth.
abstract: Cholangiocarcinoma (CCA) is a devastating biliary cancer. Melatonin is synthesized in the pineal gland and peripheral organs from serotonin by two enzymes, serotonin N-acetyltransferase (AANAT) and acetylserotonin O-methyltransferase (ASMT). Cholangiocytes secrete neuroendocrine factors, including serotonin-regulating CCA growth by autocrine mechanisms. Melatonin exerts its effects by interaction with melatonin receptor type 1A/1B (MT1/MT2) receptors. We propose that 1) in CCA, there is decreased expression of AANAT and ASMT and secretion of melatonin, changes that stimulate CCA growth; and 2) in vitro overexpression of AANAT decreases CCA growth. We evaluated the 1) expression of AANAT, ASMT, melatonin, and MT1/MT2 in human nonmalignant and CCA lines and control and CCA biopsy samples; 2) melatonin levels in nonmalignant and CCA lines, and bile and serum from controls and patients with intrahepatic CCA; 3) effect of melatonin on the growth and expression of AANAT/ASMT and MT1/MT2 in CCA lines implanted into nude mice; and 4) effect of AANAT overexpression on the proliferation, apoptosis, and expression of MT1/MT2 in Mz-ChA-1 cells. The expression of AANAT, ASMT, and melatonin decreased, whereas MT1/MT2 expression increased in CCA lines and biopsy samples. Melatonin secretion decreased in the supernatant of CCA lines and bile of CCA patients. Melatonin decreased xenograft CCA tumor growth in nude mice by increased AANAT/ASMT and melatonin, along with reduced MT1/MT2 expression. Overexpression of AANAT in Mz-ChA-1 cells inhibited proliferation and MT1/MT2 expression and increased apoptosis. There is dysregulation of the AANAT/ASMT/melatonin → melatonin receptor axis in CCA, which inhibited melatonin secretion and subsequently enhanced CCA growth.
authors.affiliation: Division Research, Central Texas Veterans Health Care System, Tempe, USA.
authors.forename: Yuyan
authors.initials: Y
authors.lastname: Han
authors.forename: Sharon
authors.initials: S
authors.lastname: Demorrow
authors.forename: Pietro
authors.initials: P
authors.lastname: Invernizzi
authors.forename: Qing
authors.initials: Q
authors.lastname: Jing
authors.forename: Shannon
authors.initials: S
authors.lastname: Glaser
authors.forename: Anastasia
authors.initials: A
authors.lastname: Renzi
authors.forename: Fanyin
authors.initials: F
authors.lastname: Meng
authors.forename: Julie
authors.initials: J
authors.lastname: Venter
authors.forename: Francesca
authors.initials: F
authors.lastname: Bernuzzi
authors.forename: Mellanie
authors.initials: M
authors.lastname: White
authors.forename: Heather
authors.initials: H
authors.lastname: Francis
authors.forename: Ana
authors.initials: A
authors.lastname: Lleo
authors.forename: Marco
authors.initials: M
authors.lastname: Marzioni
authors.forename: Paolo
authors.initials: P
authors.lastname: Onori
authors.forename: Domenico
authors.initials: D
authors.lastname: Alvaro
authors.forename: Guido
authors.initials: G
authors.lastname: Torzilli
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Alpini
mesh_terms: D000121:Acetylserotonin O-Methyltransferase / Q000096:biosynthesis*; D000818:Animals; D017209:Apoptosis; D047068:Arylalkylamine N-Acetyltransferase / Q000096:biosynthesis*; D019898:Autocrine Communication; D001650:Bile Duct Neoplasms; D001653:Bile Ducts, Intrahepatic / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018281:Cholangiocarcinoma / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D015536:Down-Regulation; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008550:Melatonin / Q000502:physiology* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D044122:Receptor, Melatonin, MT1 / Q000096:biosynthesis*; D044123:Receptor, Melatonin, MT2 / Q000096:biosynthesis*
chemical_list: D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D000121:Acetylserotonin O-Methyltransferase; D047068:Arylalkylamine N-Acetyltransferase; D008550:Melatonin