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Epidermal growth factor–induced pyruvate dehydrogenase kinase 1 expression enhances head and neck squamous cell carcinoma metastasis via up‐regulation of fibronectin
Author(s) -
Hsu JinnYuan,
Chang JangYang,
Chang KwangYu,
Chang WenChang,
Chen BenKuen
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201700156r
Subject(s) - cancer research , head and neck squamous cell carcinoma , pyruvate kinase , basal cell , metastasis , head and neck , fibronectin , lactate dehydrogenase , epidermal growth factor , medicine , cell , chemistry , oncology , enzyme , cancer , glycolysis , head and neck cancer , metabolism , biochemistry , receptor , surgery
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 via 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 via up‐regulation of fibronectin. FASEB J. 31, 4265‐4276 (2017). www.fasebj.org