Antitumor activity of ALK1 in pancreatic carcinoma cells

In this study, the authors investigated the expression of activin receptor‐like kinase 1 (ALK1) in pancreatic carcinoma and evaluated its potential role as a tumor suppressor in vitro and in vivo. Endogenous ALK1 expression was demonstrated by immunohistochemistry in both pancreatic tumor tissue and...

Full description

Saved in:
Bibliographic Details
Published in:International journal of cancer 2007-04, Vol.120 (8), p.1641-1651
Main Authors: Ungefroren, Hendrik, Schniewind, Bodo, Groth, Stephanie, Chen, Wen‐Bin, Müerköster, Susanne Sebens, Kalthoff, Holger, Fändrich, Fred
Format: Article
Language:English
Subjects:
Activin Receptors, Type I - genetics
Activin Receptors, Type I - metabolism
activin receptor‐like kinase 1
Adenocarcinoma - genetics
Adenocarcinoma - therapy
Animals
Antigens, Differentiation - metabolism
Biological and medical sciences
Cell Cycle Proteins - metabolism
Cell Differentiation
Cell Proliferation
Cells, Cultured
Epithelial Cells - metabolism
Female
GADD45beta
Gastroenterology. Liver. Pancreas. Abdomen
Gene Expression Regulation, Neoplastic - physiology
Genes, Tumor Suppressor - physiology
Humans
Immunoblotting
Immunohistochemistry
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Medical sciences
Mesoderm - cytology
Mesoderm - metabolism
Mice
Mice, Inbred BALB C
Mice, SCID
Nuclear Proteins - metabolism
p38
p38 Mitogen-Activated Protein Kinases - metabolism
pancreatic carcinoma
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - therapy
Promoter Regions, Genetic
Receptors, Transforming Growth Factor beta - metabolism
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger - metabolism
Signal Transduction
Smad Proteins - metabolism
TGF‐beta
Transcriptional Activation
Transfection
Transforming Growth Factor beta - metabolism
Tumors
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:In this study, the authors investigated the expression of activin receptor‐like kinase 1 (ALK1) in pancreatic carcinoma and evaluated its potential role as a tumor suppressor in vitro and in vivo. Endogenous ALK1 expression was demonstrated by immunohistochemistry in both pancreatic tumor tissue and peritumoral normal tissue from 6 patients and by RT‐PCR in 8/12 established pancreatic cancer cell lines. Ectopic expression of a constitutively active (ca) ALK1 mutant in TGF‐β sensitive PANC‐1 and COLO‐357 cells augmented transcriptional activation of a Smad2/3 responsive reporter, and slowed down basal growth in vitro. Both effects were further enhanced by TGF‐β/ALK5 stimulation, suggesting largely independent nuclear Smad signaling by both type I receptors. Upon orthotopic transplantation of PANC‐1‐caALK1 into immunodeficient mice, tumor size was strongly reduced and was associated with a lower microvessel density in the PANC‐1‐caALK1‐derived tumors. In vitro, this mutant efficiently blocked TGF‐β‐induced epithelial‐to‐mesenchymal transdifferentiation and suppressed TGF‐β/ALK5‐mediated activation of the p38 MAPK pathway. Mechanistically, caALK1 silenced MyD118, an immediate TGF‐β target gene whose protein product, GADD45β, couples Smad signaling to p38 activation. These results show that ALK1 activation in pancreatic tumor cells is antioncogenic by inducing ALK5‐independent growth inhibition and by blocking TGF‐β/ALK5‐mediated epithelial‐to‐mesenchymal transdifferentiation and, possibly, invasion and metastatic progression. © 2007 Wiley‐Liss, Inc.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.22393