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Dephosphorylation of p-ERK1/2 in relation to tumor remission after HER-2 and Raf1 blocking therapy in a conditional mouse tumor model.

Abstract
Several studies have shown that HER-2/neu (erbB-2) blocking therapy strategies can cause tumor remission. However, the responsible molecular mechanisms are not yet known. Both ERK1/2 and Akt/PKB are critical for HER-2-mediated signal transduction. Therefore, we used a mouse tumor model that allows downregulation of HER-2 in tumor tissue by administration of anhydrotetracycline (ATc). Switching-off HER-2 caused a rapid tumor remission by more than 95% within 7 d of ATc administration compared to the volume before switching-off HER-2. Interestingly, HER-2 downregulation caused a dephosphorylation of p-ERK1/2 by more than 80% already before tumor remission occurred. Levels of total ERK protein were not influenced. In contrast, dephosphorylation of p-Akt occurred later, when the tumor was already in remission. These data suggest that in our HER-2 tumor model dephosphorylation of p-ERK1/2 may be more critical for tumor remission than dephosphorylation of p-Akt. To test this hypothesis we used a second mouse tumor model that allows ATc controlled expression of BXB-Raf1 because the latter constitutively signals to ERK1/2, but cannot activate Akt/PKB. As expected, downregulation of BXB-Raf1 in tumor tissue caused a strong dephosphorylation of p-ERK1/2, but did not decrease levels of p-Akt. Interestingly, tumor remission after switching-off BXB-Raf1 was similarly efficient as the effect of HER-2 downregulation, despite the lack of p-Akt dephosphorylation. In conclusion, two lines of evidence strongly suggest that dephosphorylation of p-ERK1/2 and not that of p-Akt is critical for the rapid tumor remission after downregulation of HER-2 or BXB-Raf1 in our tumor model: (i) dephosphorylation of p-ERK1/2 but not that of p-Akt precedes tumor remission after switching-off HER-2 and (ii) downregulation of BXB-Raf1 leads to a similarly efficient tumor remission as downregulation of HER-2, although no p-Akt dephosphorylation was observed after switching-off BXB-Raf1.
AuthorsCarolin K Hausherr, Ilka B Schiffer, Susanne Gebhard, Andreas Banić, Berno Tanner, Heinz Kolbl, Eric Thoenes, Thomas Beckers, Christian Spangenberg, Dirk Prawitt, Tatjana Trost, Bernhard Zabel, Franz Oesch, Matthias Hermes, Jan G Hengstler
JournalMolecular carcinogenesis (Mol Carcinog) Vol. 45 Issue 5 Pg. 302-8 (May 2006) ISSN: 0899-1987 [Print] United States
PMID16496387 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright(c) 2006 Wiley-Liss, Inc.
Chemical References
  • Tetracyclines
  • 4-epianhydrotetracycline
  • Receptor, ErbB-2
  • Proto-Oncogene Proteins c-raf
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
Topics
  • Animals
  • Blotting, Western
  • Disease Models, Animal
  • Down-Regulation
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Mitogen-Activated Protein Kinase 1 (metabolism)
  • Mitogen-Activated Protein Kinase 3 (metabolism)
  • NIH 3T3 Cells
  • Neoplasms, Experimental (genetics, metabolism, prevention & control)
  • Phosphorylation
  • Proto-Oncogene Proteins c-raf (antagonists & inhibitors, metabolism)
  • Receptor, ErbB-2 (antagonists & inhibitors, metabolism)
  • Remission Induction
  • Signal Transduction
  • Tetracyclines (pharmacology)
  • Transfection

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