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rdf:type |
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lifeskim:mentions |
umls-concept:C0017262,
umls-concept:C0023467,
umls-concept:C0034818,
umls-concept:C0086418,
umls-concept:C0185117,
umls-concept:C0202220,
umls-concept:C0597298,
umls-concept:C0597357,
umls-concept:C1280500,
umls-concept:C1533691,
umls-concept:C1613914,
umls-concept:C1999216,
umls-concept:C2911684
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pubmed:issue |
19
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pubmed:dateCreated |
2009-10-2
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pubmed:abstractText |
The insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R) are receptor tyrosine kinases that participate in mitogenic and antiapoptotic signaling in normal and neoplastic epithelia. In the present study, immunoblotting and reverse transcription-PCR demonstrated expression of IGF1R and IR isoform A in acute myelogenous leukemia (AML) cell lines as well as in >80% of clinical AML isolates. Treatment with insulin enhanced signaling through the Akt and MEK1/2 pathways as well as survival of serum-starved AML cell lines. Conversely, treatment with BMS-536924, a dual IGF1R/IR kinase inhibitor that is undergoing preclinical testing, inhibited constitutive receptor phosphorylation as well as downstream signaling through MEK1/2 and Akt. These changes inhibited proliferation and, in some AML cell lines, induced apoptosis at submicromolar concentrations. Likewise, BMS-536924 inhibited leukemic colony formation in CD34+ clinical AML samples in vitro. Collectively, these results not only indicate that expression of IGF1R and IR isoform A is common in AML but also show that interruption of signaling from these receptors inhibits proliferation in clinical AML isolates. Accordingly, further investigation of IGF1R/IR axis as a potential therapeutic target in AML appears warranted.
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pubmed:grant |
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pubmed:commentsCorrections |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Oct
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pubmed:issn |
1538-7445
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pubmed:author |
pubmed-author:AttarRicardoR,
pubmed-author:CarboniJoan MJM,
pubmed-author:ErlichmanCharlesC,
pubmed-author:GottardisMarcoM,
pubmed-author:HaluskaPaulP,
pubmed-author:KarpJudith EJE,
pubmed-author:KaufmannScott HSH,
pubmed-author:LoegeringDavid ADA,
pubmed-author:PetersonKevin LKL,
pubmed-author:SchneiderPaula APA,
pubmed-author:SmithB DouglasBD,
pubmed-author:Wahner HendricksonAndrea EAE
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pubmed:issnType |
Electronic
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pubmed:day |
1
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pubmed:volume |
69
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
7635-43
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pubmed:dateRevised |
2011-9-26
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pubmed:meshHeading |
pubmed-meshheading:19789352-Benzimidazoles,
pubmed-meshheading:19789352-Cell Growth Processes,
pubmed-meshheading:19789352-HL-60 Cells,
pubmed-meshheading:19789352-Humans,
pubmed-meshheading:19789352-Insulin-Like Growth Factor I,
pubmed-meshheading:19789352-K562 Cells,
pubmed-meshheading:19789352-Leukemia, Myeloid, Acute,
pubmed-meshheading:19789352-Protein Isoforms,
pubmed-meshheading:19789352-Protein Kinase Inhibitors,
pubmed-meshheading:19789352-Pyridones,
pubmed-meshheading:19789352-Receptor, IGF Type 1,
pubmed-meshheading:19789352-Receptor, Insulin,
pubmed-meshheading:19789352-Signal Transduction,
pubmed-meshheading:19789352-Tumor Cells, Cultured,
pubmed-meshheading:19789352-U937 Cells
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pubmed:year |
2009
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pubmed:articleTitle |
Expression of insulin receptor isoform A and insulin-like growth factor-1 receptor in human acute myelogenous leukemia: effect of the dual-receptor inhibitor BMS-536924 in vitro.
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pubmed:affiliation |
Departments of Medicine and Oncology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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