Linked Life Data

17363506

Source:http://linkedlifedata.com/resource/pubmed/id/17363506

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2007-3-16
pubmed:abstractText
Constitutive activation of the phosphatidylinositol-3-kinase (PI3K)-Akt signaling pathway is associated with the neoplastic phenotype in many human tumor cell types. Given the antiapoptotic role of this pathway, we examined whether its specific blockade might sensitize human tumor cells to the induction of apoptosis by various anticancer drugs. Although specific blockade of the PI3K-Akt pathway alone with inhibitors such as LY294002 did not induce cell death, it resulted in marked and selective enhancement of the induction of apoptosis by microtubule-destabilizing agents such as vincristine. This effect was apparent only in tumor cells in which the PI3K-Akt pathway is constitutively activated. Blockade of the PI3K-Akt pathway induced the activation of glycogen synthase kinase-3beta, which phosphorylates microtubule-associated proteins such as tau and thereby reduces their ability to bind and stabilize microtubules. The consequent destabilization of microtubules induced by the inhibition of PI3K-Akt signaling appeared to increase their sensitivity to low concentrations of microtubule-destabilizing agents that alone do not lead to the disruption of cytoplasmic microtubules in tumor cells. Such a synergistic effect on microtubule integrity was not apparent for stable microtubules in the neurites of neuronal cells. These results suggest that the administration of a combination of a PI3K-Akt pathway inhibitor and a microtubule-destabilizing agent is a potential chemotherapeutic strategy for the treatment of tumor cells in which this signaling pathway is constitutively activated.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
1535-7163
pubmed:author
pubmed:issnType
Print
pubmed:volume
6
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1133-42
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:17363506-Antineoplastic Agents, pubmed-meshheading:17363506-Apoptosis, pubmed-meshheading:17363506-Cell Communication, pubmed-meshheading:17363506-Cell Differentiation, pubmed-meshheading:17363506-Chromones, pubmed-meshheading:17363506-Enzyme Inhibitors, pubmed-meshheading:17363506-Flow Cytometry, pubmed-meshheading:17363506-Fluorescent Antibody Technique, pubmed-meshheading:17363506-Humans, pubmed-meshheading:17363506-Microtubules, pubmed-meshheading:17363506-Morpholines, pubmed-meshheading:17363506-Neoplasms, pubmed-meshheading:17363506-Neurons, pubmed-meshheading:17363506-Phosphatidylinositol 3-Kinases, pubmed-meshheading:17363506-Phosphorylation, pubmed-meshheading:17363506-Proto-Oncogene Proteins c-akt, pubmed-meshheading:17363506-Signal Transduction, pubmed-meshheading:17363506-Tubulin, pubmed-meshheading:17363506-Tubulin Modulators, pubmed-meshheading:17363506-Tumor Cells, Cultured, pubmed-meshheading:17363506-Vincristine
pubmed:year
2007
pubmed:articleTitle
Blockade of the phosphatidylinositol-3-kinase-Akt signaling pathway enhances the induction of apoptosis by microtubule-destabilizing agents in tumor cells in which the pathway is constitutively activated.
pubmed:affiliation
Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't