A kinase-independent biological activity for insulin growth factor-1 receptor (IGF-1R) : implications for inhibition of the IGF-1R signal

Oncotarget. 2013 Mar;4(3):463-73. doi: 10.18632/oncotarget.886.

Abstract

It has been demonstrated that epidermal growth factor receptor (EGFR) can have kinase independent activity. EGFR kinase-independent function maintains intracellular glucose levels via sodium glucose transporter protein 1 (SGLT1) and supports cell survival. It is plausible that this phenomenon can apply to other receptor tyrosine kinases. We found that transfection of insulin-like growth factor receptor (IGF-1R) siRNA into HEK293 (human embryonic kidney) and MCF7 (metastatic breast cancer) cells result in decreased intracellular glucose levels, whereas treatment with an IGF-1R tyrosine kinase inhibitor OSI-906 did not affect intracellular glucose levels. In addition, IGF-1R interacted with SGLT1 in a manner similar to that previously reported with EGFR. The combination of IGF-1R siRNA and OSI-906 resulted in decreased viability of HEK293 and MCF7 cell lines compared to either agent alone. Collectively, these experiments suggest that IGF-1R, has kinase-independent biologic functions and provide a rationale for combining anti-IGF-1R antibodies or siRNA and IGF-1R small molecule inhibitors.

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Blotting, Western
  • Cell Cycle / drug effects
  • Cell Cycle / genetics
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Flow Cytometry
  • Glucose / metabolism*
  • HEK293 Cells
  • Humans
  • Imidazoles / pharmacology
  • Intracellular Space / metabolism
  • MCF-7 Cells
  • Pyrazines / pharmacology
  • RNA Interference
  • Receptor, IGF Type 1 / antagonists & inhibitors
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Sodium-Glucose Transporter 1 / genetics
  • Sodium-Glucose Transporter 1 / metabolism*

Substances

  • 3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol
  • Imidazoles
  • Pyrazines
  • SLC5A1 protein, human
  • Sodium-Glucose Transporter 1
  • Receptor, IGF Type 1
  • Glucose