Linked Life Data

18436711

Source:http://linkedlifedata.com/resource/pubmed/id/18436711

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2008-6-20
pubmed:abstractText
Transcriptional changes in response to hypoxia are regulated in part through mitogen-activated protein (MAP) kinase signaling to activator protein 1 (AP-1), and thus contribute to resistance of cancer cells to therapy, including platinum compounds. A key role for JNK in pro-apoptotic signaling in hypoxic cells has previously been established. Here we analyze hypoxic signaling through MAPK kinases to AP-1/c-Jun in the HT29 colon adenocarcinoma cell line, and observe activation of stress-activated pathways mediated predominantly by SEK1 and MKK7. In transient transfection assays, introduction of dominant-negative constructs for both MKK7 and SEK1 abolished hypoxia-induced AP-1 activation. Functional studies of the pathway using HT29-derived cell lines stably expressing mutant SEK1 or MKK7 showed impaired activation of Jun NH2-terminal kinase (JNK) and AP-1 in response to hypoxia, more marked in MKK7-deficient than SEK1-deficient cells. Inhibition of SEK1 rendered hypoxic cells more sensitive to oxaliplatin in vitro, whereas the opposite effect was observed in MKK7-deficient cells. The mutant cell lines grown as mouse xenografts were treated with oxaliplatin, bevacizumab, or both. The SEK1-deficient tumors exhibited greater sensitivity to all treatments, whereas MKK7-deficient cells were resistant in vivo, consistent with in vitro observations. These data support a positive contribution of MKK7/JNK to oxaliplatin cytotoxicity and identify SEK1 as a potential target for reversal of hypoxic resistance to oxaliplatin.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Angiogenesis Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/Antibodies, Monoclonal, http://linkedlifedata.com/resource/pubmed/chemical/Antibodies, Monoclonal, Humanized, http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents, http://linkedlifedata.com/resource/pubmed/chemical/MAP Kinase Kinase 4, http://linkedlifedata.com/resource/pubmed/chemical/MAP Kinase Kinase 7, http://linkedlifedata.com/resource/pubmed/chemical/Organoplatinum Compounds, http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-jun, http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factor AP-1, http://linkedlifedata.com/resource/pubmed/chemical/bevacizumab, http://linkedlifedata.com/resource/pubmed/chemical/oxaliplatin
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
1521-0111
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
74
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
246-54
pubmed:dateRevised
2011-11-17
pubmed:meshHeading
pubmed:year
2008
pubmed:articleTitle
Disruption of signaling through SEK1 and MKK7 yields differential responses in hypoxic colon cancer cells treated with oxaliplatin.
pubmed:affiliation
Abramson Family Cancer Center, University of Pennsylvania, 1020 BRB II/III, 421 Curie Blvd., Philadelphia, PA 19104, USA. vasilevs@mail.med.upenn.edu
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural