title: Inhibition of ADAM17 reduces hypoxia-induced brain tumor cell invasiveness.
abstract: 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.
authors.affiliation: Department of Neurology, Henry Ford Health Sciences Center, Detroit, Michigan 48202, USA.
authors.forename: Xuguang
authors.initials: X
authors.lastname: Zheng
authors.forename: Feng
authors.initials: F
authors.lastname: Jiang
authors.forename: Mark
authors.initials: M
authors.lastname: Katakowski
authors.forename: Steven N
authors.initials: SN
authors.lastname: Kalkanis
authors.forename: Xin
authors.initials: X
authors.lastname: Hong
authors.forename: Xuepeng
authors.initials: X
authors.lastname: Zhang
authors.forename: Zheng Gang
authors.initials: ZG
authors.lastname: Zhang
authors.forename: Hongyan
authors.initials: H
authors.lastname: Yang
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D015153:Blotting, Western; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D005910:Glioma / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D018316:Gliosarcoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D009025:Morpholines; D011799:Quinazolines; D034741:RNA, Small Interfering; C099410:TAPI-2; D020032:Tyrphostins; C101044:RTKI cpd; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D051722:ADAM Proteins; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606464:Adam17 protein, rat