PMID- 21878656
OWN - NLM
STAT- MEDLINE
DCOM- 20120315
LR  - 20201113
IS  - 1538-8514 (Electronic)
IS  - 1535-7163 (Linking)
VI  - 10
IP  - 11
DP  - 2011 Nov
TI  - Antitumoral effects of calcitriol in basal cell carcinomas involve inhibition of 
      hedgehog signaling and induction of vitamin D receptor signaling and 
      differentiation.
PG  - 2179-88
LID - 10.1158/1535-7163.MCT-11-0422 [doi]
AB  - 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.
FAU - Uhmann, Anja
AU  - Uhmann A
AD  - Institute of Human Genetics, University of Goettingen, Heinrich-Duker-Weg 12, 
      37073 Goettingen, Germany. auhmann@gwdg.de
FAU - Niemann, Hannah
AU  - Niemann H
FAU - Lammering, Berenice
AU  - Lammering B
FAU - Henkel, Cornelia
AU  - Henkel C
FAU - Hess, Ina
AU  - Hess I
FAU - Nitzki, Frauke
AU  - Nitzki F
FAU - Fritsch, Anne
AU  - Fritsch A
FAU - Prufer, Nicole
AU  - Prufer N
FAU - Rosenberger, Albert
AU  - Rosenberger A
FAU - Dullin, Christian
AU  - Dullin C
FAU - Schraepler, Anke
AU  - Schraepler A
FAU - Reifenberger, Julia
AU  - Reifenberger J
FAU - Schweyer, Stefan
AU  - Schweyer S
FAU - Pietsch, Torsten
AU  - Pietsch T
FAU - Strutz, Frank
AU  - Strutz F
FAU - Schulz-Schaeffer, Walter
AU  - Schulz-Schaeffer W
FAU - Hahn, Heidi
AU  - Hahn H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110830
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Hedgehog Proteins)
RN  - 0 (Oncogene Proteins)
RN  - 0 (PTCH1 protein, human)
RN  - 0 (Patched Receptors)
RN  - 0 (Patched-1 Receptor)
RN  - 0 (Ptch1 protein, mouse)
RN  - 0 (Receptors, Calcitriol)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (Trans-Activators)
RN  - 0 (Zinc Finger Protein GLI1)
RN  - FXC9231JVH (Calcitriol)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Calcitriol/*pharmacology
MH  - Carcinoma, Basal Cell/genetics/*metabolism
MH  - Cell Differentiation/drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Hedgehog Proteins/*antagonists & inhibitors/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Mutation
MH  - Oncogene Proteins/metabolism
MH  - Patched Receptors
MH  - Patched-1 Receptor
MH  - Receptors, Calcitriol/*metabolism
MH  - Receptors, Cell Surface/genetics
MH  - Signal Transduction/*drug effects
MH  - Trans-Activators/metabolism
MH  - Zinc Finger Protein GLI1
EDAT- 2011/09/01 06:00
MHDA- 2012/03/16 06:00
CRDT- 2011/09/01 06:00
PHST- 2011/09/01 06:00 [entrez]
PHST- 2011/09/01 06:00 [pubmed]
PHST- 2012/03/16 06:00 [medline]
AID - 1535-7163.MCT-11-0422 [pii]
AID - 10.1158/1535-7163.MCT-11-0422 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2011 Nov;10(11):2179-88. doi: 10.1158/1535-7163.MCT-11-0422. 
      Epub 2011 Aug 30.