Open AccessIGF‐1 receptor is down‐regulated by sunitinib induces MDM2‐dependent ubiquitination
Author(s) -
Shen Hongchang,
Fang Yan,
Dong Wei,
Mu Xueru,
Liu Qi,
Du Jiajun
Publication year - 2012
Publication title -
febs open bio
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.718
H-Index - 31
ISSN - 2211-5463
DOI - 10.1016/j.fob.2011.12.001
Subject(s) - sunitinib , mapk/erk pathway , transfection , signal transduction , ubiquitin , hek 293 cells , protein kinase b , phosphorylation , cancer research , receptor tyrosine kinase , tyrosine kinase , microbiology and biotechnology , receptor , mdm2 , chemistry , biology , cell culture , medicine , biochemistry , cancer , apoptosis , genetics , gene
The insulin like growth factor receptor subtype 1(IGF‐1R) plays an important role in cancers transformation and progression. The aim is to investigate the effects of sunitinib on IGF‐1R cell signaling transduction, especially on receptor phosphorylation and ubiquitination. In HEK293 cells, IGF‐1R signaling pathways are activated in response to IGF‐1, which induces obvious phosphorylations of receptor tyrosine and Akt, ERK. However, the phosphorylations of receptor tyrosine, Akt and ERK were significant inhibited by sunitinib. We found that both IGF‐1 and sunitinib obviously down regulated the IGF‐1R expression. For analysis the ubiquitination, HEK293 cells were simulated with 100 ng/ml IGF‐1 or 10 nM sunitinib for 10 min after serum starvation for 24 h. Both IGF‐1 and sunitinib could obviously induce the IGF‐1R ubiquitination at 10 min compared with control (only serum free, no stimulation), indicating IGF‐1 and sunitinib down‐regulate the IGF‐1R by increasing the receptor degradation through ubiquitination dependent proteasome pathway. We also found that MDM2 combined to IGF‐1R in response to sunitinib stimulation. To confirm it, HEK293 cells were transfected with human HA‐MDM2 (+MDM2) or siRNA to MDM2 (−MDM2). Following 24 h serum starvation, cells were stimulated with 10 nM sunitinib for 10 min. In over‐expressed MDM2 cells, IGF‐1R was more ubiquitinated than that in mock‐transfected cells (control), and no ubiquitination in −MDM2 cells. These results mean that sunitinib mediates ubiquitination of IGF‐1R dependent on MDM2. In summary, sunitinib could block signaling transduction and mediate degradation of IGF‐1R.