Inhibition of IGF-I receptor signaling in combination with rapamycin or temsirolimus increases MYC-N phosphorylation.
BACKGROUND
It has been previously shown that blockade of the type 1 insulin-like growth factor receptor (IGF1R) signaling combined with mTOR inhibition decreased neuroblastoma proliferation in vitro. MYC-N inactivation occurs through phosphorylation by downstream elements of the IGF1R signaling pathway. It was hypothesized that inhibition of IGF1R signaling would increase the inactivation of MYC-N.


METHODS
BE-2(c) and IMR-32 neuroblastoma cell lines were treated with varying concentrations of alphaIR3, rapamycin and temsirolimus either alone or in combination and the expression of MYC-N and phosphorylated MYC-N proteins were evaluated by Western blotting. The number of apoptotic cells was evaluated through cleaved caspase-3 expression.


RESULTS
IGF1R signaling blockade in combination with mTOR inhibition decreased MYC-N protein expression, increased MYC-N phosphorylation and significantly increased cleaved caspase-3 expression in treated cells.


CONCLUSIONS
The combination of rapamycin or temsirolimus with alphaIR3 decreases MYC-N expression, increases MYC-N phosphorylation and induces apoptosis in vitro which may have clinical relevance to children with neuroblastoma.
Coulter
Don W
DW
Division of Hematology-Oncology, Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE 68198-2165, U.S.A. dcoulter@chsomaha.org
Wilkie
Mary Beth
MB
Moats-Staats
Billie M
BM
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D006801:Humans; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured
C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; C401859:temsirolimus; D017526:Receptor, IGF Type 1; D020123:Sirolimus