EGF–induced PDK1 expression enhances HNSCC metastasis via up-regulation of fibronectin

What is it about?

Epidermal growth factor receptor (EGFR) activation is amajor cause ofmetastasis in such cancers as head and neck squamous cell carcinoma (HNSCC); however, whether the metabolic enzyme, pyruvate dehydrogenase kinase 1 (PDK1), mediates EGF-enhanced HNSCC metastasis remains unclear. Of interest, we found that EGF induced PDK1 expression in HNSCC. Tumor cell transformation induced by EGF was repressed by PDK1 knockdown, and the down-regulation of PDK1 expression or inhibition of its activity significantly blocked EGFenhanced cellmigration and invasion. In addition, depletion of PDK1 impeded EGF-enhanced binding ofHNSCC cells to endothelial cells as well as the metastatic seeding of tumor cells in lungs. PDK1 depletion inhibited EGFinducedmatrixmetalloproteinase-1 (MMP-1),MMP-2,MMP-3,MMP-9, and fibronectin expression andRac1/cdc42 activation. Furthermore, PDK1 overexpression induced MMP-1, MMP-2, MMP-3, MMP-9, and fibronectin expression and Rac1/cdc42 activation. Of interest, depletion of fibronectin inhibited PDK1-enhancedMMP-1–3 and MMP-9 expression as well as Rac1/cdc42 activation and tumor invasion. These results demonstrate that EGFinduced PDK1 expression enhances HNSCC metastasis via activation of the fibronectin signaling pathway. Inhibition of PDK1may be a potential strategy for the treatment of EGFR-mediatedHNSCC metastasis.

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Why is it important?

These results demonstrate that EGFinduced PDK1 expression enhances HNSCC metastasis via activation of the fibronectin signaling pathway. Inhibition of PDK1may be a potential strategy for the treatment of EGFR-mediatedHNSCC metastasis.

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