Increased local dopamine secretion has growth-promoting effects in cholangiocarcinoma

Monique Coufal, Pietro Invernizzi, Eugenio Gaudio, Francesca Bernuzzi, Gabriel A. Frampton, Paolo Onori, Antonio Franchitto, Guido Carpino, Jonathan C. Ramirez, Domenico Alvaro, Marco Marzioni, Guido Battisti, Antonio Benedetti, Sharon DeMorrow

Research output: Contribution to journalArticle

31 Scopus citations

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 have previously shown that serotonin metabolism is dysregulated in cholangiocarcinoma leading to an increased secretion of serotonin, which has growth-promoting effects. Because serotonin and dopamine share the degradation machinery, we evaluated the secretion of dopamine from cholangiocarcinoma and its effects on cell proliferation. Using 4 cholangiocarcinoma cell lines and human biopsy samples, we demonstrated that there was an increase in mRNA and protein expression of the dopamine synthesis enzymes tyrosine hydroxylase and dopa decarboxylase in cholangiocarcinoma. There was increased dopamine secretion from cholangiocarcinoma cell lines compared to H69 and HIBEC cholangiocytes and increased dopamine immunoreactivity in human biopsy samples. Furthermore, administration of dopamine to all cholangiocarcinoma cell lines studied increased proliferation by up to 30%, which could be blocked by the pretreatment of the D2 and D4 dopamine receptor antagonists, whereas blocking dopamine production by a-methyldopa administration suppressed growth by up to 25%. Administration of α-methyldopa to nude mice also suppressed cholangiocarcinoma tumor growth. The data presented here represent the first evidence that dopamine metabolism is dysregulated in cholangiocarcinoma and that modulation of dopamine synthesis may represent an alternative target for the development of therapeutic strategies.

Original languageEnglish (US)
Pages (from-to)2112-2122
Number of pages11
JournalInternational Journal of Cancer
Volume126
Issue number9
DOIs
StatePublished - May 1 2010
Externally publishedYes

Keywords

  • Biliary cancer
  • Biogenic amines
  • Dopa decarboxylase
  • Monoamine oxidase A
  • Tyrosine hydroxylase

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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    Coufal, M., Invernizzi, P., Gaudio, E., Bernuzzi, F., Frampton, G. A., Onori, P., Franchitto, A., Carpino, G., Ramirez, J. C., Alvaro, D., Marzioni, M., Battisti, G., Benedetti, A., & DeMorrow, S. (2010). Increased local dopamine secretion has growth-promoting effects in cholangiocarcinoma. International Journal of Cancer, 126(9), 2112-2122. https://doi.org/10.1002/ijc.24909