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

Abstract

<jats:p>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 D<jats:sub>3</jats:sub>, calcitriol, inhibits Hh signaling and proliferation of murine ERMS<jats:italic>in vivo</jats:italic>and<jats:italic>in vitro</jats:italic>. Concomitantly, calcitriol activates vitamin D receptor (Vdr) signaling and induces tumor differentiation. In addition, calcitriol inhibits ERMS growth in<jats:italic>Ptch</jats:italic>-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.</jats:p>

A Functional and Putative Physiological Role of Calcitriol in Patched1/Smoothened Interaction

“…The treatment of the transfected cells was conducted in duplicates for each medium. Similar results were carried out after 4 and 8 h incubation of M2H-transfected NIH-3T3 cells with wt Ptch or Ptch ITZ Enhances the Antitumoral Potential of Calcitriol-Calcitriol efficiently inhibits Hh signaling and proliferation and stimulates differentiation processes in Ptch-associated cancers in mice (17,26). Moreover, the inhibitory effect of calcitriol on Hh signaling is still detectable when Hh signaling is constitutively activated due to the expression of the oncogene SMO-M2 (Fig.…”

“…Recently we described that the oxysterol calcitriol, a twice hydroxylated vitamin D 3 derivative, efficiently inhibits Hh signaling of Ptch-associated tumors and Hh-stimulated wt Ptch and Ptch Ϫ/Ϫ cells (17,26). Moreover, we demonstrated that calcitriol inhibits Hh signaling downstream of Ptch but upstream of Gli supposedly at the level of Smo.…”

“…This fascinating fact raises the question if this binding pocket might also be a target site for Smo-inhibiting molecules, like calcitriol (17,26). Nevertheless, a study by Myers et al suggested that neither the CRD nor the 7TM are the major sites of regulation by Ptch (39).…”

“…Due to the facts that (a) Ptch shows similarities to sterol transporters (10,11), (b) Ptch Ϫ/Ϫ cells are unable to secrete Hh-inhibitory factors (16,17), (c) Smo activity is controllable by oxysterols (15,24,25) and (d) the natural occurring oxysterol calcitriol efficiently inhibits Hh signaling (17,26) it is tempting to speculate that calcitriol might be an endogenous mediator of Ptch/Smo interaction and Smo inhibition.…”

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

“…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).…”