The role of cyclooxygenase-2 and pyruvate dehydrogenase kinase 1 in epidermal growth factor-enhanced head and neck squamous cell carcinoma metastasis

Abstract

Epidermal growth factor receptor (EGFR) activation is a major cause of metastasis in many cancers such as head and neck squamous cell carcinoma (HNSCC) While it is well known that inflammatory factors and metabolic diseases have been associated with the development of cancer the regulation and functional role of inflammation-triggered cyclooxygenase-2 (COX-2) and metabolic enzyme pyruvate dehydrogenase kinase 1 (PDK1) in EGF-enhanced HNSCC metastasis remain unclear Interestingly we found that EGF induced COX-2 and PDK1 expression mainly in HNSCC The tumor cell transformation induced by EGF was repressed by either COX-2 or PDK1 knockdown The repression by COX-2 knockdown was eliminated when cells were treated with EGF and prostaglandin E2 (PGE2) Either down-regulation or inhibition of COX-2 and PDK1 significantly blocked EGF-enhanced cell migration and invasion In addition PGE2 compensated for the reduction in migration and invasion in COX-2-knockdown cells Either COX-2 or PDK1 depletion inhibited EGF-induced matrix metalloproteinase-1 (MMP-1) MMP-2 MMP-3 MMP-9 and fibronectin expression and Rac1/cdc42 activation The inhibitory effect of COX-2 depletion on MMPs and the fibronectin/Rac1/cdc42 axis were reversed by co-treatment with PGE2 Furthermore depletion of fibronectin impeded the COX-2-enhanced binding of HNSCC cells to endothelial cells and tumor cell metastatic seeding of the lungs Depletion of PDK1 also impeded the EGF-enhanced binding of HNSCC cells to endothelial cells and tumor cell metastatic seeding of the lungs as well as COX-2 knockdown These results demonstrate that EGF-induced COX-2 and PDK1 expression enhances HNSCC metastasis via activation of the fibronectin signaling pathway The inhibition of expression and activation of COX-2 and PDK1 would be a potential strategy for the treatment of EGFR-mediated HNSCC metastasis

Date of Award	2015 Sept 10
Original language	English
Supervisor	Ben-Kuen Chen (Supervisor)