Insulin-like growth factor-1 receptor and ligand targeting in head and neck squamous cell carcinoma.
IGF-1 receptor (IGF-1R) signaling is associated with increased tumorigenesis of epithelial cancers. In light of recent epidemiological studies correlating high circulating levels of IGF-1 with increased risk of second primary tumors (SPTs) of the head and neck, we examined IGF system and epidermal growth factor receptor (EGFR) expression in human head and neck squamous cell carcinoma (HNSCC) matched pairs and a cross-section of HNSCC cell lines. Employing the latter, we demonstrated that IGF-1 stimulated S-phase transition in a PI 3-K/Akt and Erk-dependent manner in 5 of 8 cell lines, with Erk activation being dependent upon EGFR kinase activity. IGF-1 stimulated thymidine incorporation was inhibited by treatment with IGFBP-3, the IGF-1R tyrosine kinase inhibitor NVP-AEW541, or the EGFR tyrosine kinase inhibitor AG1478. Combining IGFBP-3 with NVP-AEW541 or AG1478 abrogated IGF-1 responses at 10-fold lower doses than either compound alone. These results demonstrate the potential for co-targeting the IGF system and EGFR in HNSCC.
Slomiany
Mark G
MG
Department of Cell and Molecular Pharmacology and Experimental Therapeutics and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
Black
Leigh Ann
LA
Kibbey
Megan M
MM
Tingler
Melissa A
MA
Day
Terry A
TA
Rosenzweig
Steven A
SA
D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism*; D008024:Ligands; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism*
D018969:Insulin-Like Growth Factor Binding Proteins; D008024:Ligands; D047428:Protein Kinase Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt