Linked Life Data

16648553

Source:http://linkedlifedata.com/resource/pubmed/id/16648553

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2006-5-1
pubmed:abstractText
The endothelin-1 (ET-1) axis represents a novel target in several malignancies, including ovarian carcinoma. Upon being activated, the endothelin A receptor (ET(A)R) mediates multiple tumor-promoting activities, including mitogenesis, escape from apoptosis, angiogenesis, metastasis-related protease activation, epithelial-mesenchymal transition, and invasion. Integrin-linked kinase (ILK) is a multidomain focal adhesion protein that conveys intracellular signaling elicited by beta1-integrin and growth factor receptors. In this study, we investigate whether the signaling triggered by ET(A)R leading to an aggressive phenotype is mediated by an ILK-dependent mechanism. In HEY and OVCA 433 ovarian carcinoma cell lines, activation of ET(A)R by ET-1 enhances the expression of alpha2beta1 and alpha3beta1 integrins. ILK activity increases as ovarian cancer cells adhere to type I collagen through beta1 integrin signaling, and do so to a greater extent on ET-1 stimulation. ET-1 increases ILK mRNA and protein expression and activity in a time- and concentration-dependent manner. An ILK small-molecule inhibitor (KP-392) or transfection with a dominant-negative ILK mutant effectively blocks the phosphorylation of downstream signals, Akt and glycogen synthase kinase-3beta. The blockade of ET-1/ET(A)R-induced ILK activity results in an inhibition of matrix metalloproteinase activation as well as of cell motility and invasiveness in a phosphoinositide 3 kinase-dependent manner. In ovarian carcinoma xenografts, ABT-627, a specific ET(A)R antagonist, suppresses ILK expression, Akt and glycogen synthase kinase-3beta phosphorylation, and tumor growth. These data show that ILK functions as a downstream mediator of the ET-1/ET(A)R axis to potentiate aggressive cellular behavior. Thus, the ILK-related signaling cascade can be efficiently targeted by pharmacologic blockade of ET(A)R.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
1535-7163
pubmed:author
pubmed:issnType
Print
pubmed:volume
5
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
833-42
pubmed:dateRevised
2007-11-15
pubmed:meshHeading
pubmed-meshheading:16648553-Animals, pubmed-meshheading:16648553-Base Sequence, pubmed-meshheading:16648553-Cell Line, Tumor, pubmed-meshheading:16648553-Chemotaxis, pubmed-meshheading:16648553-DNA Primers, pubmed-meshheading:16648553-Endothelin-1, pubmed-meshheading:16648553-Female, pubmed-meshheading:16648553-Humans, pubmed-meshheading:16648553-Immunoblotting, pubmed-meshheading:16648553-Mice, pubmed-meshheading:16648553-Mice, Nude, pubmed-meshheading:16648553-Neoplasm Invasiveness, pubmed-meshheading:16648553-Ovarian Neoplasms, pubmed-meshheading:16648553-Protein-Serine-Threonine Kinases, pubmed-meshheading:16648553-RNA, Small Interfering, pubmed-meshheading:16648553-Receptor, Endothelin A, pubmed-meshheading:16648553-Reverse Transcriptase Polymerase Chain Reaction, pubmed-meshheading:16648553-Transplantation, Heterologous
pubmed:year
2006
pubmed:articleTitle
Integrin-linked kinase functions as a downstream mediator of endothelin-1 to promote invasive behavior in ovarian carcinoma.
pubmed:affiliation
Laboratory of Molecular Pathology and Ultrastructure, Regina Elena Cancer Institute, Via delle Messi D'Oro 156, 00158 Rome, Italy.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't