1. Disruption of the protein interaction between FAK and IGF-1R inhibits melanoma tumor growth.
- Author
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Ucar DA, Kurenova E, Garrett TJ, Cance WG, Nyberg C, Cox A, Massoll N, Ostrov DA, Lawrence N, Sebti SM, Zajac-Kaye M, and Hochwald SN
- Subjects
- Apoptosis drug effects, Blotting, Western, Cell Line, Cell Proliferation drug effects, Cell Survival drug effects, Flow Cytometry, Humans, Immunohistochemistry, Immunoprecipitation, In Situ Nick-End Labeling, Melanoma drug therapy, Melanoma metabolism, Protein Kinase Inhibitors therapeutic use, Purine Nucleosides therapeutic use, RNA, Small Interfering genetics, Signal Transduction physiology, Focal Adhesion Kinase 1 metabolism, Melanoma physiopathology, Protein Kinase Inhibitors pharmacology, Purine Nucleosides pharmacology, Receptor, IGF Type 1 metabolism, Signal Transduction drug effects
- Abstract
FAK (focal adhesion kinase) and IGF-1R (insulin-like growth factor receptor-1) directly interact with each other and thereby activate crucial signaling pathways that benefit cancer cells. Inhibition of FAK and IGF-1R function has been shown to significantly decrease cancer cell proliferation and increase sensitivity to chemotherapy and radiation treatment. As a novel approach in human melanoma, we evaluated the effect of a small-molecule compound that disrupts the protein interaction of FAK and IGF-1R. Previously, using virtual screening and functional testing, we identified a lead compound (INT2-31) that targets the known FAK-IGF-1R protein interaction site. We studied the ability of this compound to disrupt FAK-IGF-1R protein interactions, inhibit downstream signaling, decrease human melanoma cell proliferation, alter cell cycle progression, induce apoptosis and decrease tumor growth in vivo. INT2-31 blocked the interaction of FAK and IGF-1R in vitro and in vivo in melanoma cells and tumor xenografts through precluding the activation of IRS-1, leading to reduced phosphorylation of AKT upon IGF-1 stimulation. As a result, INT2-31 significantly inhibited cell proliferation and viability (range 0.05-10 μM). More importantly, 15 mg/kg of INT2-31 given for 21 d via intraperitoneal injection disrupted the interaction of FAK and IGF-1R and effectively decreased phosphorylation of tumor AKT, resulting in significant melanoma tumor regression in vivo. Our data suggest that the FAK-IGF-1R protein interaction is an important target, and disruption of this interaction with a novel small molecule (INT2-31) has potential anti-neoplastic therapeutic effects in human melanoma.
- Published
- 2012
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