Dokument

Summary:
Glioblastoma Multiforme (GBM) ist der aggressivste hirneigene Tumor mit einer schlechten Überlebensprognose. Trotz Weiterentwicklung der multimodalen Behandlungsansätze, bestehend aus Tumorresektion und Radio- sowie Chemotherapie ist die Therapie des GBM bei einem durchschnittlichen Überleben von 2 Jahren nur bedingt erfolgreich. Als Standardchemotherapie kommt heutzutage das alkylierende Chemotherapeutikum Temozolomid (TMZ, Temodal®) zum Einsatz. Ein Grund für die ineffiziente Wirksamkeit von Chemo-und Radiotherapie ist die Ausbildung von Resistenzen in den Tumorzellen. Das Verständnis der Resistenzbildung auf molekularer Ebene ist daher sehr wichtig und könnte neue Ansätze zur Optimierung der Chemo- und Radiotherapie liefern. Metalloproteasen (MPs) sind in GBMs erhöht exprimiert und stets mit einer schlechten Prognose verbunden. In dieser Studie haben wir die Expression von MPs nach TMZ-Behandlung in U87-MG Glioblastom-Zellen systematisch untersucht. Eine TMZ-Behandlung von 5 Tagen induziert in U87-MG Zellen eine erhöhte Expression von ADAM8, MMP-1, MMP-9 and MMP-14 in den überlebenden Zellen. Um die Funktion der induzierten MPs zu untersuchen, wurde der Breitband MP-Inhibitor Batimastat (BB-94) in U87-MG Zellen in Verbindung mit TMZ eingesetzt. BB-94 führt zu einer erhöhten Sensitivität von U87-MG Zellen gegenüber dem TMZ-induzierten Zelltod und verringert das durch TMZ induzierte invasive Potenzial von U87-MG Zellen. Daraus folgt, dass die durch TMZ induzierten MPs sowohl zu einer Chemoresistenz als auch zu einer Rezidiv-Bildung beitragen können. Als potenzieller Signalweg der TMZ-vermittelten MP-Induktion in U87-MG Zellen wurde eine Zunahme der ERK1/2 Phosphorylierung unter TMZ-Behandlung nachgewiesen. Die Verwendung des ERK1/2 Inhibitors UO126 führte zu einer Abnahme der TMZ-induzierten Expression von ADAM8, MMP-1 and MMP-9, aber nicht von MMP-14, was darauf hindeutet, dass es alternative Signalwege bei der Induktion von MMP-14 gibt. PS/γ-Sekretase kombiniert mit MPs führt zu einer Prozessierung von Transmembran-Proteinen, durch die zahlreiche intrazelluläre Signalwege gesteuert werden. Die Inhibition von γ-Sekretase durch DAPT hat in unseren Analysen einen vergleichbaren Effekt wie BB-94 auf die Sensitivierung von U87-MG Zellen durch TMZ, was darauf schließen lässt, dass γ-Sekretase zusammen mit MPs zu einer Chemoresistenz von Glioblastom-Zellen führen kann. Zusammenfassend lässt sich sagen, dass die Induktion der Metalloproteasen MMP-1, MMP-9, MMP-14, and ADAM8 durch TMZ eine Chemoresistenz von Glioblastom-Zellen vermitteln kann und dass diese Metalloproteasen durch die Spaltung von Membranproteinen wie z.B. CD44, Met oder Integrinen an der „DNA Damage Response“ beteiligt sind oder die Proliferation und die Invasivität von Glioblastom-Zellen fördern können. Deshalb wäre eine kombinierte Therapie von TMZ mit Metalloprotease-Inhibitoren eine mögliche Therapie-Option, um die Effizienz der Standard-TMZ-Therapie zu verbessern und die Rezidivneigung zu verhindern.

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