bay-11-7082 and Kidney-Neoplasms

Chronic low dose of tumor necrosis factor-α (TNF-α) stimulation promotes tumorigenesis by facilitating tumor proliferation and metastasis. The plasma levels of TNF-α are increased in patients with renal cell carcinoma (RCC). Furthermore, high-grade clear cell RCC cell lines secrete more TNF-α than low-grade ones, and allow low-grade cell lines' gain of invasive ability. However, the molecular mechanism of TNF-α in mediating progression of RCC cells remains unclear. In the present study, TNF-α induced epithelial-mesenchymal transition (EMT) of RCC cells by repressing E-cadherin, promoting invasiveness and activating matrix metalloproteinase (MMP) 9 activity. RCC cells underwent promoted growth in vivo following stimulation with TNF-α. In addition, TNF-α induced phosphorylation of extracellular signal-regulated kinase, nuclear factor kappa B (NF-κB) and Akt in a time-dependent manner, and increased nuclear translocation and promoter activity of NF-κB. To investigate the role of NF-κB activation in TNF-α-induced EMT of RCC, we employed chemical inhibitors (NF-κB activation inhibitor and Bay 11-7082) and transfected dominant-negative (pCMV-IκBαM) and overexpressive (pFLAG-p65) vectors of NF-κB. While overexpression of NF-κB p65 alone could induce E-cadherin loss in RCC, EMT phenotypes and MMP9 expressions induced by TNF-α were not reversed by the inhibitors of NF-κB activation. These results suggest that the TNF-α signaling pathway is involved in the tumorigenesis of RCC. However, NF-κB activation is not crucial for invasion and EMT enhanced by TNF-α in RCC cells.

Topics: Africa, Western; Animals; Carcinoma, Renal Cell; Cell Transformation, Neoplastic; Enzyme Induction; Epithelial-Mesenchymal Transition; Extracellular Signal-Regulated MAP Kinases; Humans; Kidney Neoplasms; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred NOD; NF-kappa B; Nitriles; Proto-Oncogene Proteins c-akt; Reverse Transcriptase Polymerase Chain Reaction; RNA, Neoplasm; Signal Transduction; Sulfones; Tumor Necrosis Factor-alpha