Epidermal growth factor-induced pyruvate dehydrogenase kinase 1 expression enhances head and neck squamous cell carcinoma metastasis via up-regulation of fibronectin

• Published in: The FASEB journal Vol. 31; no. 10; p. 4265
• Main Authors: Hsu, Jinn-Yuan, Chang, Jang-Yang, Chang, Kwang-Yu, Chang, Wen-Chang, Chen, Ben-Kuen
• Format: Journal Article
• Language: English
• Published: United States 01.10.2017
• Subjects: Carcinoma, Squamous Cell - metabolism; Cell Line, Tumor; Cell Movement - drug effects; Epidermal Growth Factor - metabolism; Epidermal Growth Factor - pharmacology; ErbB Receptors - metabolism; Fibronectins - metabolism; Head and Neck Neoplasms - metabolism; Humans; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - metabolism; Neoplasm Invasiveness - pathology; Protein-Serine-Threonine Kinases - metabolism; Squamous Cell Carcinoma of Head and Neck; Transcriptional Activation - drug effects; Up-Regulation - drug effects; MMP; EGF; HNSCC; PDK1
• ISSN: 1530-6860
• DOI: 10.1096/fj.201700156R

Epidermal growth factor receptor (EGFR) activation is a major cause of metastasis 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 EGF-enhanced cell migration and invasion. In addition, depletion of PDK1 impeded EGF-enhanced binding of HNSCC cells to endothelial cells as well as the metastatic seeding of tumor cells in lungs. PDK1 depletion inhibited EGF-induced matrix metalloproteinase-1 (MMP-1), MMP-2, MMP-3, MMP-9, and fibronectin expression and Rac1/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-enhanced MMP-1-3 and MMP-9 expression as well as Rac1/cdc42 activation and tumor invasion. These results demonstrate that EGF-induced PDK1 expression enhances HNSCC metastasis activation of the fibronectin signaling pathway. Inhibition of PDK1 may be a potential strategy for the treatment of EGFR-mediated HNSCC metastasis.-Hsu, J.-Y., Chang, J.-Y., Chang, K.-Y., Chang, W.-C., Chen B.-K. Epidermal growth factor-induced pyruvate dehydrogenase kinase 1 expression enhances head and neck squamous cell carcinoma metastasis up-regulation of fibronectin.