title: A multiplicity of anti-invasive effects of farnesyl transferase inhibitor SCH66336 in human head and neck cancer.
abstract: Metastasis is a critical event in the progression of head and neck squamous cell carcinoma (HNSCC) and closely correlates with clinical outcome. We previously showed that the farnesyl transferase inhibitor SCH66336 has antitumor activities in HNSCC by inducing the secretion of insulin-like growth factor binding protein 3 (IGFBP-3), which in turn inhibits tumor growth and angiogenesis. In our study, we found that SCH66336 at a sublethal dose for HNSCC inhibited the migration and invasion of HNSCC cells. The inhibitory effect of SCH66336 was associated with the blockade of the IGF-1 receptor (IGF-1R) pathway via suppressing IGF-1R itself and Akt expression. Consistent with previous work, induction of IGFBP-3 by SCH66336 also contributed in part to the anti-invasive effect. SCH66336 treatment also reduced the expression and activity of the urokinase-type plasminogen activator (uPA) and matrix metalloproteinase 2 (MMP-2), both important regulators of tumor metastasis. The effect of SCH66336 on uPA activity was inhibited partly by knockdown of IGFBP-3 using small interfering RNA. The inhibitory effect of SCH66336 on migration or invasion was attenuated partly or completely by knockdown of IGFBP-3, Akt or IGF-1R expression, respectively. Our results demonstrate that the IGF-1R pathway plays a major role in the proliferation, migration and invasion of HNSCC cells, suggesting that therapeutic obstruction of the IGF-1R pathway would be a useful approach to treating patients with HNSCC.
authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Seung Hyun
authors: SH
authors: Oh
authors: Ju-Hee
authors: JH
authors: Kang
authors: Jong
authors: J
authors: Kyu Woo
authors: Ok-Hee
authors: OH
authors: Lee
authors: Edward S
authors: ES
authors: Kim
authors: Ho-Young
authors: HY
authors: Lee
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010880:Piperidines / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000077195:Squamous Cell Carcinoma of Head and Neck; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D003986:Dibenzocycloheptenes
chemical_list: D051231:Farnesyltranstransferase; D018972:Insulin-Like Growth Factor Binding Protein 3; D020778:Matrix Metalloproteinase 2; D010880:Piperidines; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D034741:RNA, Small Interfering; D017526:Receptor, IGF Type 1; D014568:Urokinase-Type Plasminogen Activator; C115354:lonafarnib; D003986:Dibenzocycloheptenes