Activation of EGF receptor family members suppresses the cytotoxic effects of tumor necrosis factor-α |
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Authors: | Michael Hoffmann Mathias Schmidt Winfried Wels |
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Institution: | (1) Institute for Experimental Cancer Research, Tumor Biology Center, Breisacher Strasse 17, D-79106 Freiburg, Germany e-mail: wels@tumorbio.uni-freiburg.de Tel.: +49-761-206 1630; Fax: +49-761-206 1599, DE;(2) Department of Biology, University of Freiburg, Germany, DE |
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Abstract: | Tumor necrosis factor (TNF)-α has a broad range of biological activities, which depend heavily on cell type and physiological
condition. In a panel of human tumor cell lines we analyzed expression of the receptor tyrosine kinases EGFR, ErbB2 and ErbB3,
and the response to TNF-α. Among the cell lines tested those resistant to TNF-α were found to express high levels of either
EGFR, or ErbB2 and ErbB3. In TNF-sensitive breast and cervical carcinoma cells activation of EGFR or ErbB2 by the exogenous
growth factors EGF and heregulin β1 resulted in a significant increase in the number of cells surviving TNF-α treatment. In
contrast, inhibition of EGFR activation in TNF-resistant breast carcinoma cells by the novel antagonistic anti-EGFR antibody
14E1 sensitized the cells to the cytotoxic effects of TNF-α. A bacterially expressed fusion protein consisting of a 14E1 single-chain
(sc) Fv antibody fragment linked to human TNF-α retained TNF-α activity. This scFv(14E1)-TNF-α molecule localized specifically
to EGFR on the surface of tumor cells and activated the NF-κB pathway in co-cultured T cells, as demonstrated by electrophoretic
mobility shift assays.
Received: 6 May 1998 / Accepted: 16 July 1998 |
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Keywords: | TNF-α EGF receptor ErbB2 Receptor tyrosine kinase Recombinant antibody |
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