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. © 2009 UICC

Coufal, M., Invernizzi, P., Gaudio, E., Bernuzzi, F., Frampton, G., Onori, P., et al. (2010). Increased local dopamine secretion has growth-promoting effects in cholangiocarcinoma. INTERNATIONAL JOURNAL OF CANCER, 126(9), 2112-2122 [10.1002/ijc.24909].

Increased local dopamine secretion has growth-promoting effects in cholangiocarcinoma

INVERNIZZI, PIETRO;Bernuzzi, Francesca Veronica;
2010

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. © 2009 UICC
Articolo in rivista - Articolo scientifico
Biliary cancer; Biogenic amines; Dopa decarboxylase; Monoamine oxidase A; Tyrosine hydroxylase; Animals; Bile Duct Neoplasms; Cell Line, Tumor; Cell Proliferation; Cholangiocarcinoma; Dopamine; Humans; Male; Methyldopa; Mice; Mice, Inbred BALB C; Xenograft Model Antitumor Assays; Bile Ducts, Intrahepatic; Cancer Research; Oncology; Medicine (all)
English
2112
2122
11
Coufal, M., Invernizzi, P., Gaudio, E., Bernuzzi, F., Frampton, G., Onori, P., et al. (2010). Increased local dopamine secretion has growth-promoting effects in cholangiocarcinoma. INTERNATIONAL JOURNAL OF CANCER, 126(9), 2112-2122 [10.1002/ijc.24909].
Coufal, M; Invernizzi, P; Gaudio, E; Bernuzzi, F; Frampton, G; Onori, P; Franchitto, A; Carpino, G; Ramirez, J; Alvaro, D; Marzioni, M; Battisti, G; Benedetti, A; Demorrow, S
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/106402
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