The expression of hepatocyte growth factor (HGF) and c-Met is associated with tumor progression in many human malignancies. A recent study demonstrated HGF and c-Met expression in human salivary gland cancer tissues. Here, we investigated the role of the HGF/c-Met system in the invasive growth of two human salivary gland cancer cell lines: green fluorescent protein-adenoid cystic carcinoma 2 (GFP-ACC2) and GFP-ACCM. HGF enhanced the invasive growth of the two cell lines by activating P13K/Akt signaling. All Akt isoforms (Akt1, Akt2, and Akt3) were detected in both cell types by Western blot analysis. Knockdown of any of the Akt isoforms using isoform-specific synthetic small-interfering RNAs largely abrogated the invasive growth induced by HGF. Our findings suggest that all of the Akt isoforms are required for the HGF-stimulated invasive growth of human salivary gland cancer cells, and that targeting a single Akt isoform could be effective in treating salivary gland cancers. (c) 2008 Elsevier Inc. All rights reserved.