Linked Life Data

17804716

Source:http://linkedlifedata.com/resource/pubmed/id/17804716

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
17
pubmed:dateCreated
2007-9-6
pubmed:abstractText
Notch receptors are key regulators of development by controlling cell-fate determination in many multicellular organisms. Genes that are important for normal differentiation play a role in cancer when their normal functions became dysregulated. Notch signaling has been shown to promote and maintain survival of many types of cancers, and we previously have shown that Notch3 plays an important role in lung cancer. In this study, we showed that a high percentage of lung cancer lines expressed Jagged1, Notch receptors, and their transcriptional target genes (HES1, Hey1), suggesting that the Notch pathway plays an important role in lung cancer biology. Thus, inhibition of Notch receptor activation represents a compelling treatment strategy. Notch activation requires proteolytic cleavage of the receptor by gamma-secretase protein complex. In this study, we determined the ability of MRK-003, a gamma-secretase inhibitor, to inhibit Notch3 signaling, growth, and apoptosis of lung cancer cell lines in vitro and in vivo using mouse xenograft models. We also found that MRK-003 inhibited Notch3 signaling, reduced tumor cell proliferation, inhibited serum independence, and induced apoptosis. This drug had no effect when Notch3 expression was knocked down using small interfering RNA (siRNA), suggesting that the observed effects were mediated by specific action on this receptor. In conclusion, these results support the hypothesis that inhibition of Notch activation using a gamma-secretase inhibitor represents a potential new approach for the targeted therapy of lung cancer.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
67
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
8051-7
pubmed:dateRevised
2007-12-3
pubmed:meshHeading
pubmed-meshheading:17804716-Amyloid Precursor Protein Secretases, pubmed-meshheading:17804716-Animals, pubmed-meshheading:17804716-Antineoplastic Agents, pubmed-meshheading:17804716-Apoptosis Regulatory Proteins, pubmed-meshheading:17804716-Carcinoma, Non-Small-Cell Lung, pubmed-meshheading:17804716-Cell Proliferation, pubmed-meshheading:17804716-Cyclic S-Oxides, pubmed-meshheading:17804716-Disease Progression, pubmed-meshheading:17804716-Enzyme Inhibitors, pubmed-meshheading:17804716-Gene Expression Regulation, Neoplastic, pubmed-meshheading:17804716-Humans, pubmed-meshheading:17804716-Lung Neoplasms, pubmed-meshheading:17804716-Mice, pubmed-meshheading:17804716-Mice, Nude, pubmed-meshheading:17804716-Receptors, Notch, pubmed-meshheading:17804716-Signal Transduction, pubmed-meshheading:17804716-Thiadiazoles, pubmed-meshheading:17804716-Xenograft Model Antitumor Assays
pubmed:year
2007
pubmed:articleTitle
Gamma-secretase inhibitor prevents Notch3 activation and reduces proliferation in human lung cancers.
pubmed:affiliation
Division of Hematology and Medical Oncology and Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural