title: Serotonin metabolism is dysregulated in cholangiocarcinoma, which has implications for tumor growth.
abstract: Cholangiocarcinoma is a devastating cancer of biliary origin with limited treatment options. Symptoms are usually evident after blockage of the bile duct by the tumor, and at this late stage, they are relatively resistant to chemotherapy and radiation therapy. Therefore, it is imperative that alternative treatment options are explored. We present novel data indicating that the metabolism of serotonin is dysregulated in cholangiocarcinoma cell lines, compared with normal cholangiocytes, and tissue and bile from cholangiocarcinoma patients. Specifically, there was an increased expression of tryptophan hydroxylase 1 and a suppression of monoamine oxidase A expression (enzymes responsible for the synthesis and degradation of serotonin, respectively) in cholangiocarcinoma. This resulted in an increased secretion of serotonin from cholangiocarcinoma and increased serotonin in the bile from cholangiocarcinoma patients. Increased local serotonin release may have implications on cholangiocarcinoma cell growth. Serotonin administration increased cholangiocarcinoma cell growth in vitro, whereas inhibition of serotonin synthesis decreases tumor cell growth both in vitro and in vivo. The data presented here represent the first evidence that serotonin metabolism is dysregulated in cholangiocarcinoma and that modulation of serotonin synthesis may represent an alternative target for the development of therapeutic strategies.
authors.affiliation: Department of Medicine, Texas A&M Health Science Center, College of Medicine, Scott & White Hospital, Temple, TX 76504, USA.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Alpini
authors.forename: Pietro
authors.initials: P
authors.lastname: Invernizzi
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
authors.forename: Julie
authors.initials: J
authors.lastname: Venter
authors.forename: Shelley
authors.initials: S
authors.lastname: Kopriva
authors.forename: Francesca
authors.initials: F
authors.lastname: Bernuzzi
authors.forename: Paolo
authors.initials: P
authors.lastname: Onori
authors.forename: Antonio
authors.initials: A
authors.lastname: Franchitto
authors.forename: Monique
authors.initials: M
authors.lastname: Coufal
authors.forename: Gabriel
authors.initials: G
authors.lastname: Frampton
authors.forename: Domenico
authors.initials: D
authors.lastname: Alvaro
authors.forename: Sum P
authors.initials: SP
authors.lastname: Lee
authors.forename: Marco
authors.initials: M
authors.lastname: Marzioni
authors.forename: Antonio
authors.initials: A
authors.lastname: Benedetti
authors.forename: Sharon
authors.initials: S
authors.lastname: DeMorrow
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000378:metabolism* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000378:metabolism* / Q000473:pathology; D053379:Chromogranin A / Q000032:analysis; D010134:Fenclonine / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008995:Monoamine Oxidase / Q000235:genetics; D012701:Serotonin / Q000378:metabolism*
chemical_list: D053379:Chromogranin A; D012701:Serotonin; D008995:Monoamine Oxidase; D010134:Fenclonine