tapi-2 and Glioma

The membrane-anchored metalloproteinase tumor necrosis factor-alpha-converting enzyme (TACE/a disintegrin and metalloproteinase [ADAM] 17) is key in proteolytic ectodomain shedding of several membrane-bound growth factors, cytokines and receptors. The expression and activity of ADAM17 increases under some pathological conditions including stroke, and promotes neural progenitor cell migration and contributes to stroke-induced neurogenesis. Hypoxia initiates cellular invasive processes that occur under both physiological and pathological conditions such as invasion and metastasis of some tumors. In the present study, we sought to elucidate whether ADAM17 contributes to brain tumor invasion. To this end, we examined the role of ADAM17 in the invasiveness of two different brain tumor cell lines, 9L rat gliosarcoma and U87 human glioma, under normoxic and hypoxic conditions. Additionally, we tested the effects of ADAM17 suppression on in vitro tumor cell invasion by means of ADAM17 proteolytic inhibitors and specific small interfering RNA. We found that tumor cells upregulated ADAM17 expression under hypoxia, and that ADAM17 activity correlated with increased tumor cell invasion. Conversely, suppression of ADAM17 proteolysis decreased invasiveness induced by hypoxia in 9L and U87 cells. Furthermore, the contribution of ADAM17 to tumor invasion was independent of matrix metalloproteinase (MMP)-2 and MMP-9 activity. ADAM17 was also found to activate the epidermal growth factor/phosphoinositide-3 kinase/serine/threonine kinase signal transduction pathway. Our data suggest that hypoxia-induced ADAM17 contributes to glioma cell invasiveness through activation of the EGFR signal pathway.

Topics: ADAM Proteins; ADAM17 Protein; Animals; Blotting, Western; Cell Hypoxia; Cell Line, Tumor; Cell Movement; Chromones; Enzyme Inhibitors; Gene Expression; Glioma; Gliosarcoma; Humans; Hydroxamic Acids; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Microscopy, Fluorescence; Mitogen-Activated Protein Kinase 1; Morpholines; Neoplasm Invasiveness; Proto-Oncogene Proteins c-akt; Quinazolines; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; RNA, Small Interfering; Transfection; Tyrphostins

The shedding mechanism for the tomoregulin (TR) ectodomain, which contains two follistatin modules and a single epidermal growth factor (EGF)-like domain, remains unclear. Our study provides the first evidence that proinflammatory cytokines, IL-1beta and TNF-alpha, induce TR-ectodomain shedding in cultured A172 human glioma cells, without affecting TR mRNA expression. In addition, it appears that this shedding process is induced via activation of the NF-kappaB signaling pathway; with consequent increase in the production of metalloproteinases. Furthermore, since due to erbB4 tyrosine phosphorylation TR may have functions similar to EGF/neuregulin (NRG) family growth factors, our results suggest that following inflammation-induced injury, increases in TR shedding may contribute to tissue growth and repair in the central nervous system.

Topics: 3T3 Cells; Animals; Blotting, Western; Dipeptides; Glioma; Humans; Hydroxamic Acids; Interleukin-1; Membrane Proteins; Metalloendopeptidases; Mice; Neoplasm Proteins; NF-kappa B; Protein Structure, Tertiary; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha