Melatonin exerts by an autocrine loop antiproliferative effects in cholangiocarcinoma; its synthesis is reduced favoring cholangiocarcinoma growth

Yuyan Han, Sharon DeMorrow, Pietro Invernizzi, Qing Jing, Shannon Glaser, Anastasia Renzi, Fanyin Meng, Julie Venter, Francesca Bernuzzi, Mellanie White, Heather Francis, Ana Lleo, Marco Marzioni, Paolo Onori, Domenico Alvaro, Guido Torzilli, Eugenio Gaudio, Gianfranco Alpini

Research output: Contribution to journalArticle

32 Citations (Scopus)

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.

Original languageEnglish
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume301
Issue number4
DOIs
Publication statusPublished - Oct 2011

Fingerprint

Cholangiocarcinoma
Melatonin
Acetylserotonin O-Methyltransferase
Growth
Melatonin MT2 Receptor
Nude Mice
Bile
Serotonin
Melatonin MT1 Receptor
Arylalkylamine N-Acetyltransferase
Biliary Tract Neoplasms
Melatonin Receptors
Apoptosis
Biopsy
Pineal Gland
Heterografts

Keywords

  • Biliary epithelium
  • Biliary neoplasm
  • Neuroendocrine regulation

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology

Cite this

Melatonin exerts by an autocrine loop antiproliferative effects in cholangiocarcinoma; its synthesis is reduced favoring cholangiocarcinoma growth. / Han, Yuyan; DeMorrow, Sharon; Invernizzi, Pietro; Jing, Qing; Glaser, Shannon; Renzi, Anastasia; Meng, Fanyin; Venter, Julie; Bernuzzi, Francesca; White, Mellanie; Francis, Heather; Lleo, Ana; Marzioni, Marco; Onori, Paolo; Alvaro, Domenico; Torzilli, Guido; Gaudio, Eugenio; Alpini, Gianfranco.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 301, No. 4, 10.2011.

Research output: Contribution to journalArticle

Han, Y, DeMorrow, S, Invernizzi, P, Jing, Q, Glaser, S, Renzi, A, Meng, F, Venter, J, Bernuzzi, F, White, M, Francis, H, Lleo, A, Marzioni, M, Onori, P, Alvaro, D, Torzilli, G, Gaudio, E & Alpini, G 2011, 'Melatonin exerts by an autocrine loop antiproliferative effects in cholangiocarcinoma; its synthesis is reduced favoring cholangiocarcinoma growth', American Journal of Physiology - Gastrointestinal and Liver Physiology, vol. 301, no. 4. https://doi.org/10.1152/ajpgi.00118.2011
Han, Yuyan ; DeMorrow, Sharon ; Invernizzi, Pietro ; Jing, Qing ; Glaser, Shannon ; Renzi, Anastasia ; Meng, Fanyin ; Venter, Julie ; Bernuzzi, Francesca ; White, Mellanie ; Francis, Heather ; Lleo, Ana ; Marzioni, Marco ; Onori, Paolo ; Alvaro, Domenico ; Torzilli, Guido ; Gaudio, Eugenio ; Alpini, Gianfranco. / Melatonin exerts by an autocrine loop antiproliferative effects in cholangiocarcinoma; its synthesis is reduced favoring cholangiocarcinoma growth. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2011 ; Vol. 301, No. 4.
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AU - DeMorrow, Sharon

AU - Invernizzi, Pietro

AU - Jing, Qing

AU - Glaser, Shannon

AU - Renzi, Anastasia

AU - Meng, Fanyin

AU - Venter, Julie

AU - Bernuzzi, Francesca

AU - White, Mellanie

AU - Francis, Heather

AU - Lleo, Ana

AU - Marzioni, Marco

AU - Onori, Paolo

AU - Alvaro, Domenico

AU - Torzilli, Guido

AU - Gaudio, Eugenio

AU - Alpini, Gianfranco

PY - 2011/10

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N2 - 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.

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