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1alpha,25-Dihydroxy-VitaminD3 hemmt das Wachstum von Patched-assoziierten Rhabdomyosarkomen und Basaliomen

1alpha,25-Dihydroxy-VitaminD3 inhibits the growth of Patched-associated rhadomyosarkomas and basal cell carcinomas

by Iris Berenice Lammering
Doctoral thesis
Date of Examination:2011-11-02
Date of issue:2011-11-17
Advisor:Prof. Dr. Heidi Hahn
Referee:Prof. Dr. Heidi Hahn
Referee:PD Dr. Rotraut Mößner
crossref-logoPersistent Address: http://dx.doi.org/10.53846/goediss-3550

 

 

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Abstract

English

Activation of the Hedgehog (Hh)-signaling pathway due to deficiency in the Hh receptor Patched1 (Ptch) is the pivotal defect leading to formation of rhabdomyosarcomas (RMS) and basal cell carcinoma (BCC). Recent reports provided evidence of Ptch-dependent secretion of vitamin D3-related compound, which functions as an endogenous inhibitor of Hh-signaling by repressing the activity of the signal transduction partner of Ptch, Smoothened (Smo). This suggests that Ptch deficient tumor cells are devoid of this substance, which in turn results in activation of Hh-signaling. Here I show that the application of the physiologically active form of vitamin D3, calcitriol, inhibits proliferation and growth of RMS and BCC of Ptch mutant mice in vitro and in vivo. This is accompanied by the activation of the vitamin D receptor (Vdr) and inhibition of the Hh-signaling. The concomitant antiproliferative effects on RMS and BCC growth are stronger than those of the Hh-specific inhibitor cyclopamine, even though the latter more efficiently inhibits Hh-signaling. Taken together, we show that exogenous supply of calcitriol controls the activity of two independent pathways, Hh- and Vdr-signaling, which are relevant to tumorigenesis and tumor treatment. These data suggest that calcitriol could be a therapeutic option in the treatment of RMS and BCC.
Keywords: Hedgehog/Patched-signaling; 1á; 25(OH)2D3; vitamin-D-receptor-signalin; calcitriol; antitumor therapy; basal cell carcinoma; rhabdomyosarkoma

Other Languages

Die Aktivierung des Hedgehog (Hh)-Signalwegs durch Defekte im Hh-Rezeptor Patched (Ptch) führt zur Entstehung von Rhabdomysarkomen (RMS) und Basalzellkarzinomen (BCC). Kürzlich wurde gezeigt, dass Ptch eine Pumpfunktion für Vitamin D3 besitzt. Ptch übt darüber eine endogenen Inhibition des Hh-Siganlweges durch Hemmung der Aktivität des Signaltransduktionspartner von Ptch, Smoothened (Smo), aus. Dies weist darauf hin, dass Ptch-defiziente Tumorzellen an dieser Substanz verarmt sind, was im Umkehrschluss zur Aktivierung des Hh-Signalwegs führt. In dieser Arbeit zeige ich, dass die Applikation des physiologisch aktiven Vitamin D3, Calcitriol, das Wachstum und die Proliferation von RMS und BCC in Ptch-mutanten Mäusen in vitro und in vivo hemmt. Die antiproliferative Wirkung von Calcitriol wird hierbei höchstwahrscheinlich über das Zusammenspiel der Aktivierung der Vdr-Signalkaskade und der Hemmung des Hh-Signalweges vermittelt. Die Ergebnisse zeigen, dass Calcitriol als neues Medikament in der Behandlung von Ptch-assoziierten Tumoren Anwendung finden könnte. Durch seine duale Funktion könnte Calcitriol daher bisherigen Therapien von Ptch-assoziierten Tumoren, welche spezifische Hh-Antagonisten umfassen, überlegen sein.
Schlagwörter: Hedgehog/Patched-Signalweg; VitaminD-Rezeptor-Siganlweg; 1á; 25(OH)2D3; Calcitriol; Antitumor Therapie; Basalzellkarzinome; Rhabdomyosarkome
 

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