Linked Life Data

18089706

Source:http://linkedlifedata.com/resource/pubmed/id/18089706

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12 Pt 1
pubmed:dateCreated
2007-12-19
pubmed:abstractText
Elucidating signaling pathways that mediate cell survival or apoptosis will facilitate the development of targeted therapies in cancer. In neuroblastoma tumors, brain-derived neurotrophic factor (BDNF) and its receptor TrkB are associated with poor prognosis. Our previous studies have shown that BDNF activation of TrkB induces resistance to chemotherapy via activation of phosphoinositide-3-kinase (PI3K)/Akt pathway. To study targets of PI3K/Akt that mediate protection from chemotherapy, we focused on glycogen synthase kinase-3beta (GSK-3beta), which is a known modulator of apoptosis. We used pharmacologic and genetic methods to study the role of GSK-3beta in the BDNF/TrkB/PI3K/Akt protection of neuroblastoma from chemotherapy. BDNF activation of TrkB induced the Akt-dependent phosphorylation of GSK-3beta, resulting in its inactivation. Treatment of neuroblastoma cells with inhibitors of GSK-3beta, LiCl, GSK-3beta inhibitor VII, kenpaullone, or a GSK-3beta-targeted small interfering RNA (siRNA) resulted in a 15% to 40% increase in neuroblastoma cell survival after cytotoxic treatment. Transfection of neuroblastoma cells with a constitutively active GSK-3beta S9A9 caused a 10% to 15% decrease in cell survival. Using real-time, dynamic measurements of cell survival, we found that 6 to 8 h after etoposide treatment was the period during which critical events regulating the induction of cell death or BDNF/TrkB-induced protection occurred. During this period, etoposide treatment was associated with the dephosphorylation and activation of GSK-3beta in the mitochondria that was blocked by BDNF activation of TrkB. These data indicate that the inactivation of GSK-3beta contributes to the BDNF/TrkB/PI3K/Akt protection of neuroblastoma cells from chemotherapy.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
1535-7163
pubmed:author
pubmed:issnType
Print
pubmed:volume
6
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
3113-21
pubmed:dateRevised
2011-11-2
pubmed:meshHeading
pubmed:year
2007
pubmed:articleTitle
Inactivation of glycogen synthase kinase-3beta contributes to brain-derived neutrophic factor/TrkB-induced resistance to chemotherapy in neuroblastoma cells.
pubmed:affiliation
Cell and Molecular Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, 10 Center Drive MSC-1928, Bldg. 10/CRC 1-3940, Bethesda, MD 20892, USA.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Intramural