Linked Life Data

21123455

Source:http://linkedlifedata.com/resource/pubmed/id/21123455

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2011-1-17
pubmed:abstractText
Classic signaling by the proinflammatory cytokine interleukin 6 (IL-6) involves its binding to target cells that express the membrane-bound IL-6 receptor ?. However, an alternate signaling pathway exists in which soluble IL-6 receptor (sIL-6R?) can bind IL-6 and activate target cells that lack mIL-6R?, such as endothelial cells. This alternate pathway, also termed trans-signaling, serves as the major IL-6 signaling pathway in various pathologic proinflammatory conditions including cancer. Here we report that sIL-6R? is elevated in malignant ascites from ovarian cancer patients, where it is associated with poor prognosis. IL-6 trans-signaling on endothelial cells prevented chemotherapy-induced apoptosis, induced endothelial hyperpermeability, and increased transendothelial migration of ovarian cancer cells. Selective blockade of the MAPK pathway with ERK inhibitor PD98059 reduced IL-6/sIL-6R?-mediated endothelial hyperpermeability. ERK activation by the IL-6/sIL-6R? complex increased endothelial integrity via Src kinase activation and Y685 phosphorylation of VE-cadherin. Selective targeting of IL-6 trans-signaling in vivo reduced ascites formation and enhanced the taxane sensitivity of intraperitoneal human ovarian tumor xenografts in mice. Collectively, our results show that increased levels of sIL-6R? found in ovarian cancer ascites drive IL-6 trans-signaling on endothelial cells, thereby contributing to cancer progression. Selective blockade of IL-6 trans-signaling may offer a promising therapeutic strategy to improve the management of patients with advanced ovarian cancer.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
1538-7445
pubmed:author
pubmed:copyrightInfo
© 2010 AACR.
pubmed:issnType
Electronic
pubmed:day
15
pubmed:volume
71
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
424-34
pubmed:meshHeading
pubmed-meshheading:21123455-Animals, pubmed-meshheading:21123455-Antigens, CD, pubmed-meshheading:21123455-Ascites, pubmed-meshheading:21123455-Cadherins, pubmed-meshheading:21123455-Cell Adhesion, pubmed-meshheading:21123455-Cell Line, Tumor, pubmed-meshheading:21123455-Drug Synergism, pubmed-meshheading:21123455-Endothelial Cells, pubmed-meshheading:21123455-Female, pubmed-meshheading:21123455-Humans, pubmed-meshheading:21123455-Interleukin-6, pubmed-meshheading:21123455-MAP Kinase Signaling System, pubmed-meshheading:21123455-Mice, pubmed-meshheading:21123455-Mice, Inbred NOD, pubmed-meshheading:21123455-Mice, SCID, pubmed-meshheading:21123455-Mitogen-Activated Protein Kinases, pubmed-meshheading:21123455-Neovascularization, Pathologic, pubmed-meshheading:21123455-Ovarian Neoplasms, pubmed-meshheading:21123455-Paclitaxel, pubmed-meshheading:21123455-Phosphorylation, pubmed-meshheading:21123455-Receptors, Interleukin-6, pubmed-meshheading:21123455-Recombinant Fusion Proteins, pubmed-meshheading:21123455-Signal Transduction, pubmed-meshheading:21123455-Xenograft Model Antitumor Assays, pubmed-meshheading:21123455-src-Family Kinases
pubmed:year
2011
pubmed:articleTitle
IL-6 trans-signaling in formation and progression of malignant ascites in ovarian cancer.
pubmed:affiliation
Department of Oncology, National Taiwan University Hospital, Institute of Toxicology, National Taiwan University College of Medicine, Nankang, Taiwan.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't