Epidermal growth factor–induced pyruvate dehydrogenase kinase 1 expression enhances head and neck squamous cell carcinoma metastasisviaup‐regulation of fibronectin

Abstract

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.

EGFR / FAK and c‐Src signalling pathways mediate the internalisation of Staphylococcus aureus by osteoblasts

“…Fibronectin‐binding proteins (FnBPs) in the cell‐wall of S. aureus is an important component which can bind to extracellular matrix protein fibronectin, thereafter, the FnBP‐Fn‐α5β1 integrin interaction may initiate the internalisation of S. aureus into epithelial cells and endothelial cells (Ilic et al, 2004; Josse et al, 2015). It is reported that expression of fibronectin can be regulated by FAK and EGFR signalling, the deficiency of either FAK or EGFR signalling was demonstrated to result in downregulated expression of fibronectin (Hsu, Chang, Chang, Chang, & Chen, 2017; Ilic et al, 2004). Our data showed that blocking EGFR/FAK signalling suppresses S. aureus internalisation.…”

Fibronectin in Cancer: Friend or Foe

“…In the cancer metastasis that is mediated by the interaction between X-linked inhibitor of apoptosis (XIAP) and survivin but independent of inhibition of cell death, FN expression serves a downstream signaling factor to promote the metastasis process [92]. Furthermore, FN expression has often been found to mediate various metastatic-promoting mechanisms [93][94][95][96][97][98][99][100] (Figure 1B).…”

The oncogenic and prognostic role of PDK1 in the progression and metastasis of ovarian cancer

“…It had been reported that PDK1 was remarkably overexpressed in various tumors such as lung cancer [7], gastric cancer [17],glioblastoma [18], etc. [19][20][21][22][23][24][25], regulated by hypoxia-inducible factor-1α (HIF-1α) mediated [26] or Wnt/β-catenin signaling [27] and contributed to chemoresistance of ovarian cancer by activating EGFR [28]. Michelle K. Y's team had confirmed that PDK1 could promote the development of ovarian cancer especially in metastasis by modulating tumormesothelial adhesion, invasion, and angiogenesis via α5β1 integrin and JNK/IL-8 signaling [29].…”