title: Antitumoral effects of calcitriol in basal cell carcinomas involve inhibition of hedgehog signaling and induction of vitamin D receptor signaling and differentiation.
abstract: Activation of the Hedgehog (Hh)-signaling pathway due to deficiency in the Hh receptor Patched1 (Ptch) is the pivotal defect leading to formation of basal cell carcinoma (BCC). Recent reports provided evidence of Ptch-dependent secretion of vitamin D(3)-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, we show that the application of the physiologically active form of vitamin D(3), calcitriol, inhibits proliferation and growth of BCC of Ptch mutant mice in vitro and in vivo. This is accompanied by the activation of the vitamin D receptor (Vdr) and induction of BCC differentiation. In addition, calcitriol inhibits Hh signaling at the level of Smo in a Vdr-independent manner. The concomitant antiproliferative effects on 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 2 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 BCC, the most common tumor in humans.
authors: Institute of Human Genetics, University of Goettingen, Heinrich-Düker-Weg 12, 37073 Goettingen, Germany. auhmann@gwdg.de
authors: Anja
authors: A
authors: Uhmann
authors: Hannah
authors: H
authors: Niemann
authors: Bérénice
authors: B
authors: Lammering
authors: Cornelia
authors: C
authors: Henkel
authors: Ina
authors: I
authors: Hess
authors: Frauke
authors: F
authors: Nitzki
authors: Anne
authors: A
authors: Fritsch
authors: Nicole
authors: N
authors: Prüfer
authors: Albert
authors: A
authors: Rosenberger
authors: Christian
authors: C
authors: Dullin
authors: Anke
authors: A
authors: Schraepler
authors: Julia
authors: J
authors: Reifenberger
authors: Stefan
authors: S
authors: Schweyer
authors: Torsten
authors: T
authors: Pietsch
authors: Frank
authors: F
authors: Strutz
authors: Walter
authors: W
authors: Schulz-Schaeffer
authors: Heidi
authors: H
authors: Hahn
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002117:Calcitriol / Q000494:pharmacology*; D002280:Basal Cell Carcinoma / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D015513:Oncogene Proteins / Q000378:metabolism; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D018167:Receptors, Calcitriol / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1
chemical_list: D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; D015513:Oncogene Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D018167:Receptors, Calcitriol; D011956:Receptors, Cell Surface; D015534:Trans-Activators; D000071676:Zinc Finger Protein GLI1; D002117:Calcitriol