Abstract
The farnesyl transferase inhibitor (FTI) SCH66336 has been shown to have antitumor activities in head and neck squamous cell carcinoma (HNSCC) in vitro and in vivo. However, its mechanism of action has not been well defined. Here, we report that the insulin-like growth factor (IGF) binding protein (IGFBP)-3 mediates antitumor activities of SCH66336 in HNSCC by inhibiting angiogenesis. SCH66336 significantly suppressed HNSCC tumor growth and angiogenesis via mechanisms that are independent of H-Ras and RhoB. By inducing IGFBP-3 secretion from HNSCC cells, this compound suppresses angiogenic activities of endothelial cells, including vessel formation in chorioallantoic membranes of chick, endothelial cell sprouting from chick aorta, and capillary tube formation of human umbilical vascular endothelial cells (HUVEC). Knockdown of IGFBP-3 expression in HNSCC cells by RNA interference or depletion of IGFBP-3 in HUVECs by neutralizing antibody effectively blocked the effects of IGFBP-3 secreted from SCH66336-treated HNSCC cells on HUVECs. These findings suggest that IGFBP-3 could be a primary target for antitumor activities of FTIs and that IGFBP-3 is an effective therapeutic approach against angiogenesis in HNSCC.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Animals
-
Aorta / drug effects
-
Aorta / metabolism
-
Carcinoma, Non-Small-Cell Lung
-
Carcinoma, Squamous Cell / drug therapy*
-
Carcinoma, Squamous Cell / metabolism
-
Carcinoma, Squamous Cell / pathology
-
Cell Proliferation / drug effects
-
Chickens
-
Chorioallantoic Membrane / drug effects
-
Chorioallantoic Membrane / metabolism
-
Endothelium, Vascular / cytology
-
Endothelium, Vascular / drug effects
-
Endothelium, Vascular / metabolism
-
Enzyme Inhibitors / pharmacology
-
Farnesyltranstransferase / antagonists & inhibitors*
-
Farnesyltranstransferase / metabolism
-
Female
-
Gene Expression Regulation, Neoplastic / drug effects*
-
Genes, ras / physiology
-
Head and Neck Neoplasms / drug therapy*
-
Head and Neck Neoplasms / metabolism
-
Head and Neck Neoplasms / pathology
-
Humans
-
Insulin-Like Growth Factor Binding Protein 3 / metabolism*
-
Mice
-
Mice, Nude
-
Neovascularization, Pathologic / drug therapy*
-
Piperidines / pharmacology*
-
Pyridines / pharmacology*
-
Tumor Cells, Cultured
-
Umbilical Veins / cytology
-
Umbilical Veins / drug effects
-
Umbilical Veins / metabolism
-
Vascular Endothelial Growth Factor A / metabolism
-
rhoB GTP-Binding Protein / metabolism
Substances
-
Enzyme Inhibitors
-
Insulin-Like Growth Factor Binding Protein 3
-
Piperidines
-
Pyridines
-
Vascular Endothelial Growth Factor A
-
Farnesyltranstransferase
-
rhoB GTP-Binding Protein
-
lonafarnib