Focal Adhesion Signaling in Hepatocellular Carcinoma (HCC): Inhibition Induces Apoptosis
Abstracts
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INTRODUCTION: Focal adhesion kinase (FAK) is pivitol in adhesion signaling. It is upregulated in many human tumors, but its role in HCC is unknown. Inhibition of adhesion signaling leads to apoptosis, a process that can be regulated by the carboxyl-terminal domain of FAK (called FRNK, a negative regulator of adhesion signaling). We hypothesized that FAK would be upregulated in human HCC tumors and HCC cell lines and inhibition of adhesion signaling in these cells would lead to apoptosis. METHODS: Lysates from resected hepatocellular tumors (HCC, n=3; adenoma, n=2), and their matched non-tumor tissue, and HCC cell lines (n=4) were analyzed by immunoblotting for FAK expression and activation. Inhibition of adhesion signaling was induced by infecting cells with either a replication deficient type 5 adenoviral vector expressing green fluorescent protein (GFP) [control] or the fusion protein GFP-FRNK (MOI of 4). Apoptosis was evaluated by nucleosome assay and flow cytometry. RESULTS: FAK (total or activated) is upregulated in human HCC compared to benign tumors or normal liver. Aggressive HCC cell lines expressed more activated FAK than the less aggressive cell lines. Inhibition of FAK signaling stimulated apoptosis in the HCC cell lines up to 50%. CONCLUSION: HCC cell lines and human tumors express elevated levels of total FAK or activated FAK. Inhibition of adhesion signals stimulates apoptosis, indicating that FAK plays an integral role in adhesion signaling in HCC. Inhibition of this signaling pathway might be exploited as a therapeutic strategy in cancer patients. |
