Antitumoral Effects of Calcitriol in Basal Cell Carcinomas Involve Inhibition of Hedgehog Signaling and Induction of Vitamin D Receptor Signaling and Differentiation

Uhmann, Anja; Niemann, Hannah; Lammering, Bérénice; Henkel, Cornelia; Heß, Ina; Nitzki, Frauke; Fritsch, Anne; Prüfer, Nicole; Rosenberger, Albert; Dullin, Christian; Schraepler, Anke; Reifenberger, Julia; Schweyer, Stefan; Pietsch, Torsten; Strutz, Frank; Schulz‐Schaeffer, Walter; Hahn, Heidi

doi:10.1158/1535-7163.mct-11-0422

Cited by 68 publications

(64 citation statements)

References 39 publications

(46 reference statements)

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“…39,116,118,134,135 These processes are regulated by cell-specific mechanisms and involve inhibition of hedgehog, β -catenin, NF κ B, and PI3K signaling pathways (refs 134,136,137 reviewed in refs 127,138). Apoptosis is also regulated by vitamin D. 1,25(OH) 2 D3-induced programmed cell death is mainly due to downregulation of the anti-apoptotic proteins Bcl-2 and Bcl-X L , upregulation of pro-apoptotic BAX, GOS2, DAP-3, FADD, and caspases (reviewed in refs 69,127,139).…”

Section: Vitamin D In a ‘Nutshell’mentioning

confidence: 99%

Vitamin D signaling and melanoma: role of vitamin D and its receptors in melanoma progression and management

Slominski

Brożyna

Żmijewski

et al. 2017

Laboratory Investigation

116

128

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Ultraviolet B (UVB), in addition to having carcinogenic activity, is required for the production of vitamin D3 (D3) in the skin which supplies >90% of the body's requirement. Vitamin D is activated through hydroxylation by 25-hydroxylases (CYP2R1 or CYP27A1) and 1α-hydroxylase (CYP27B1) to produce 1,25(OH)2D3, or through the action of CYP11A1 to produce mono-di- and trihydroxy-D3 products that can be further modified by CYP27B1, CYP27A1, and CYP24A1. The active forms of D3, in addition to regulating calcium metabolism, exert pleiotropic activities, which include anticarcinogenic and anti-melanoma effects in experimental models, with photoprotection against UVB-induced damage. These diverse effects are mediated through an interaction with the vitamin D receptor (VDR) and/or as most recently demonstrated through action on retinoic acid orphan receptors (ROR)α and RORγ. With respect to melanoma, low levels of 25(OH)D are associated with thicker tumors and reduced patient survival. Furthermore, single-nucleotide polymorphisms of VDR and the vitamin D-binding protein (VDP) genes affect melanomagenesis or disease outcome. Clinicopathological analyses have shown positive correlation between low or undetectable expression of VDR and/or CYP27B1 in melanoma with tumor progression and shorter overall (OS) and disease-free survival (DFS) times. Paradoxically, this correlation was reversed for CYP24A1 (inactivating 24-hydroxylase), indicating that this enzyme, while inactivating 1,25(OH)2D3, can activate other forms of D3 that are products of the non-canonical pathway initiated by CYP11A1. An inverse correlation has been found between the levels of RORα and RORγ expression and melanoma progression and disease outcome. Therefore, we propose that defects in vitamin D signaling including D3 activation/inactivation, and the expression and activity of the corresponding receptors, affect melanoma progression and the outcome of the disease. The existence of multiple bioactive forms of D3 and alternative receptors affecting the behavior of melanoma should be taken into consideration when applying vitamin D management for melanoma therapy.

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Section: Vitamin D In a ‘Nutshell’mentioning

confidence: 99%

Vitamin D signaling and melanoma: role of vitamin D and its receptors in melanoma progression and management

Slominski

Brożyna

Żmijewski

et al. 2017

Laboratory Investigation

116

128

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“…Importantly, we recently demonstrated that calcitriol inhibits growth of basal cell carcinoma (BCC), which is an Hh/Ptch-driven tumor [18]. In BCC, the antitumoral property of calcitriol is accompanied by activation of the Vdr signaling pathway, by induction of differentiation and by simultaneous inhibition of Hh signaling activity [18].…”

Section: Introductionmentioning

confidence: 99%

Calcitriol Inhibits Hedgehog Signaling and Induces Vitamin D Receptor Signaling and Differentiation in thePatchedMouse Model of Embryonal Rhabdomyosarcoma

Uhmann

Niemann

Lammering

et al. 2012

Sarcoma

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Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Aberrant Hedgehog (Hh) signaling is characteristic of the embryonal subtype (ERMS) and of fusion-negative alveolar RMS. In the mouse, ERMS-like tumors can be induced by mutations in the Hh receptor Patched1 (Ptch). As in humans these tumors show increased Hh pathway activity. Here we demonstrate that the treatment with the active form of vitamin D3, calcitriol, inhibits Hh signaling and proliferation of murine ERMSin vivoandin vitro. Concomitantly, calcitriol activates vitamin D receptor (Vdr) signaling and induces tumor differentiation. In addition, calcitriol inhibits ERMS growth inPtch-mutant mice, which is, however, a rather late response. Taken together, our results suggest that exogenous supply of calcitriol could be beneficial in the treatment of RMS, especially in those which are associated with aberrant Hh signaling activity.

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“…The expression of the Hedgehog molecules was inhibited by 1α,25(OH) 2 D 3 in mouse skin cells in a VDR-dependent manner [60]. In basal cell carcinoma, vitamin D 3 or 1α,25(OH) 2 D 3 inhibited Hedgehog signaling by repressing GLI1 mRNA and exerted anti-proliferative effects in vitro and in vivo [61,62]. Vitamin D 3 (cholecalciferol) also inhibited Hedgehog signaling by repressing GLI2 expression and tumor growth of renal carcinoma xenografts [63].…”

Section: Regulation Of Stem Cell Signaling By Vitamin D In Solid Tumentioning

confidence: 99%

Targeting cancer stem cells in solid tumors by vitamin D

Suh

2015

The Journal of Steroid Biochemistry and Molecular Biology

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Cancer stem cells (CSCs) are a small subset of cells that may be responsible for initiation, progression and recurrence of tumors. Recent studies have demonstrated that CSCs are highly tumorigenic and resistant to conventional chemotherapies, making them a promising target for the development of preventive/therapeutic agents. A single or combination of various markers, such as CD44, EpCAM, CD49f, CD133, CXCR4, ALDH-1 and CD24, were utilized to isolate CSCs fromvarious types of human cancers. Notch, Hedgehog, Wnt, and TGF-β signalingregulate self-renewal and differentiation of normal stem cells andare aberrantly activated in CSCs. In addition, many studies have demonstrated that these stem cell-associated signaling pathways are required for the maintenance of CSCs in differentmalignancies, including breast, colorectal, prostate and pancreatic cancers. Accumulating evidence hasshowninhibitory effects of vitamin D and its analogs on the cancer stem cell signaling pathways, suggesting vitamin D as a potential preventive/therapeutic agent against CSCs.In this review, we summarize recent findings about the roles of Notch, Hedgehog, Wnt, and TGF-β signaling in CSCs as well as the effects of vitamin D on these stem cell signaling pathways.

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Antitumoral Effects of Calcitriol in Basal Cell Carcinomas Involve Inhibition of Hedgehog Signaling and Induction of Vitamin D Receptor Signaling and Differentiation

Cited by 68 publications

References 39 publications

Vitamin D signaling and melanoma: role of vitamin D and its receptors in melanoma progression and management

Vitamin D signaling and melanoma: role of vitamin D and its receptors in melanoma progression and management

Calcitriol Inhibits Hedgehog Signaling and Induces Vitamin D Receptor Signaling and Differentiation in thePatchedMouse Model of Embryonal Rhabdomyosarcoma

Targeting cancer stem cells in solid tumors by vitamin D

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