Einfluss der zellulären Östradiolantwort auf die therapeutische Inhibition von Wachstumsfaktor-Signalwegen

Zusammenfassung

Die zelluläre Antwort auf Östrogenstimuli wird über verschiedene Signalwege vermittelt. Neben dem klassischen Mechanismus der Aktivierung von Östrogenrezeptoren und deren Bindung an Ö strogen „Response Elements” (ERE) sind die non-nukleären Wirkungen des Östradiols in den letzten Jahren immer mehr in den Mittelpunkt des Interesses getreten. Dabei erwies sich die Östradiol-induzierte Aktivierung von zytoplasmatischen Kinasen der Wachstumsfaktor-Signalwege als ein wichtiger Mechanismus der zellulären Ö stradiolantwort. Vor diesem Hintergrund entstand die Frage, inwieweit Östradiol-Stimuli die Wirksamkeit von antitumoralen Substanzen schwächen können, welche gegen die Rezeptor-Tyrosinkinase(RTK)-Signaltransduktion gerichtet sind. Dabei zeigte sich tatsächlich, dass Östrogene in der Lage zu sein scheinen, die Wirksamkeit von HER2-gerichteten Therapeutika negativ zu beeinflussen. In dieser Übersicht werden die neuen Erkenntnisse über die nicht-genomischen Effekte von Östrogenen ebenso dargestellt wie die neuesten Einblicke in die molekularen Mechanismen der Östradiol-induzierten Wirkungshemmung von Trastuzumab (Herceptin™), wie sie am Modell endometrialer Tumorzellen untersucht wurden.

Abstract

Cellular response to estradiol stimuli ist mediated by different signal transduction cascades. In addition to classical mechanisms like the activation of estrogen response elements, there is increasing interest in the so-called non- nuclear actions of estrogens. It has been shown, that the estradiol-induced activation of cytoplasmic kinases is an important alternative mechanism of the cellular estradiol response. Consequently, the question has been raised, whether estradiol-induced activation of growth factor signaling would be able to interfere with the action of antitumoral substances directed against receptor-tyrosine kinase signal transduction. Recent data demonstrated, that estradiol is able to diminish the effects of antitumoral drugs targeting the HER2 receptor in vitro. Novel insights into the non-nuclear estradiol response and its impact on the efficacy of antitumoral drugs observed in endometrial tumor cells are reviewed.

Östrogene - Wachstumsfaktoren - Signaltransduktion - HER2

Estrogene - growth factor - signal transduction - HER2

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