title: A kinase-independent biological activity for insulin growth factor-1 receptor (IGF-1R) : implications for inhibition of the IGF-1R signal.
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.
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. fjanku@mdanderson.org
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Huang
authors.forename: Laura S
authors.initials: LS
authors.lastname: Angelo
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D005434:Flow Cytometry; D005947:Glucose / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D042541:Intracellular Space / Q000378:metabolism; D061986:MCF-7 Cells; D011719:Pyrazines / Q000494:pharmacology; D034622:RNA Interference; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051269:Sodium-Glucose Transporter 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; D007093:Imidazoles; D011719:Pyrazines; C495674:SLC5A1 protein, human; D051269:Sodium-Glucose Transporter 1; D017526:Receptor, IGF Type 1; D005947:Glucose