Document Detail


Insulin-like growth factor 1 receptor antibody induces rhabdomyosarcoma cell death via a process involving AKT and Bcl-x(L).
MedLine Citation:
PMID:  20818434     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Insulin-like growth factors (IGFs) and their receptor, IGF-1 receptor (IGF1R), have important roles in growth, development, stress response, aging and cancer. There are many agents that inhibit IGF1R in oncology clinical development, and in some cases, they have been associated with rapid tumor regression. However, it is not clear by which process these targeted agents induce cancer cell death and how to predict such tumor responses. Here, we showed that IGF1R antibody led to rapid cell death and tumor regression in some rhabdomyosarcoma (RMS) cells. Mechanistic analysis revealed a rapid onset of mitochondrial-dependent apoptosis, including mitochondrial depolarization, cytochrome C release and the activation of specific caspases. The antibody sensitive cells had greater dependence on AKT for maintaining downstream signaling and the expression of a constitutively active AKT, which restored AKT-signaling in these cells, inhibited anti-IGF1R induced cell death. Further analysis showed IGF1R antibody-induced hypophosphorylation of BAD and activation of downstream BAX. Interestingly, the examination of RMS cell lines and tumors revealed an inverse correlation between elevated IGF1R and Bcl-2 level (P=0.033), with the sensitive cells lacking Bcl-2 expression. The overexpression of BAD specific target, Bcl-x(L), conferred resistance, whereas Bcl-x(L) knockdown sensitized cells lacking Bcl-2 to anti-IGF1R-induced cell death. We propose that RMS pathogenesis involves increased IGF1R expression that enhances AKT and Bcl-x(L)-mediated cell survival, and the blockage of IGF1R results in inhibition of survival signal from Bcl-x(L) and cell death in the sensitive Bcl-2 negative cells.
Authors:
L H Mayeenuddin; Y Yu; Z Kang; L J Helman; L Cao
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural     Date:  2010-09-06
Journal Detail:
Title:  Oncogene     Volume:  29     ISSN:  1476-5594     ISO Abbreviation:  Oncogene     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-12-02     Completed Date:  2011-01-06     Revised Date:  2013-03-13    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  6367-77     Citation Subset:  IM    
Affiliation:
Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4265, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antibodies / therapeutic use*
Apoptosis*
Cell Line, Tumor
Female
Humans
Mice
Mitochondria / physiology
Proto-Oncogene Proteins c-akt / physiology*
Proto-Oncogene Proteins c-bcl-2 / analysis
Receptor, IGF Type 1 / analysis,  physiology*
Rhabdomyosarcoma / pathology,  therapy*
Signal Transduction
Xenograft Model Antitumor Assays
bcl-2-Associated X Protein / metabolism
bcl-Associated Death Protein / metabolism
bcl-X Protein / physiology*
Grant Support
ID/Acronym/Agency:
N01-CO-12400/CO/NCI NIH HHS; ZIC BC011048-03/BC/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antibodies; 0/BAD protein, human; 0/BAX protein, human; 0/BCL2L1 protein, human; 0/Proto-Oncogene Proteins c-bcl-2; 0/bcl-2-Associated X Protein; 0/bcl-Associated Death Protein; 0/bcl-X Protein; EC 2.7.10.1/Receptor, IGF Type 1; EC 2.7.11.1/Proto-Oncogene Proteins c-akt
Comments/Corrections

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