Secretin inhibits cholangiocarcinoma growth via dysregulation of the cAMP-dependent signaling mechanisms of secretin receptor.
Secretin plays a key role in the regulation of normal cholangiocyte physiology via secretin receptor (SCTR). SCTR expression is upregulated during extrahepatic cholestasis induced by bile duct ligation and closely associated with cholangiocyte proliferative responses. Although well studied in normal cholangiocytes, the role of secretin and the expression of SCTR in the regulation of cholangiocarcinoma proliferation are unknown. In vitro, secretin (10(-7) M) displayed differential effects on normal cholangiocyte [H-69 and human intrahepatic biliary epithelial cell line (HIBEpiC)] and cholangiocarcinoma (Mz-ChA-1, HuH-28, TFK-1, SG231, CCLP1 and HuCC-T1) cell lines as such secretin is mitogenic for normal cholangiocytes and antiproliferative for cholangiocarcinoma. As expected in normal cholangiocytes (HIBEpiC), secretin increased intracellular cyclic adenosine monophosphate (cAMP) levels. However, the effect of secretin on intracellular cAMP levels was suppressed in Mz-ChA-1 cells. Secretin-stimulated intracellular cAMP levels in Mz-ChA-1 were restored by pretreatment with pertussis toxin, suggesting that the receptor coupled to Galpha(i) rather than Galpha(s). SCTR expression was found to be downregulated in 4 of the 6 cholangiocarcinoma cell lines evaluated and in human cholangiocarcinoma biopsy samples. In vivo, secretin significantly inhibited the tumor size and more than doubled tumor latency, which was associated with a decrease in proliferating cell nuclear antigen and an increase in cleaved-caspase 3 expression levels. Our results demonstrate that secretin and/or the modulation of SCTR expression might have potential as a therapeutic tool in the treatment of cholangiocarcinoma.
Onori
Paolo
P
Experimental Medicine, University of L'Aquila, L'Aquila, Italy.
Wise
Candace
C
Gaudio
Eugenio
E
Franchitto
Antonio
A
Francis
Heather
H
Carpino
Guido
G
Lee
Vien
V
Lam
Ian
I
Miller
Timothy
T
Dostal
David E
DE
Glaser
Shannon S
SS
D001650:Bile Duct Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000473:pathology*; D000242:Cyclic AMP / Q000502:physiology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D016133:Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011964:Receptors, Gastrointestinal Hormone / Q000378:metabolism*; D012633:Secretin / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D043562:Receptors, G-Protein-Coupled; D011964:Receptors, Gastrointestinal Hormone; C029937:secretin receptor; D012633:Secretin; D000242:Cyclic AMP