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Title: Calcipotriol Targets LRP6 to Inhibit Wnt Signaling in Pancreatic Cancer.

Authors: Arensman, Michael D; Nguyen, Phillip; Kershaw, Kathleen M; Lay, Anna R; Ostertag-Hill, Claire A; Sherman, Mara H; Downes, Michael; Liddle, Christopher; Evans, Ronald M; Dawson, David W

Published In Mol Cancer Res, (2015 Nov)

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy in need of more effective treatment approaches. One potential therapeutic target is Wnt/β-catenin signaling, which plays important roles in PDAC tumor initiation and progression. Among Wnt inhibitors with suitable in vivo biologic activity is vitamin D, which is known to antagonize Wnt/β-catenin signaling in colorectal cancer and have antitumor activity in PDAC. For this study, the relationship between vitamin D signaling, Wnt/β-catenin activity, and tumor cell growth in PDAC was investigated through the use of calcipotriol, a potent non-hypercalcemic vitamin D analogue. PDAC tumor cell growth inhibition by calcipotriol was positively correlated with vitamin D receptor expression and Wnt/β-catenin activity. Furthermore, vitamin D and Wnt signaling activity were found to be reciprocally linked through feedback regulation. Calcipotriol inhibited autocrine Wnt/β-catenin signaling in PDAC cell lines in parallel with decreased protein levels of the low-density lipoprotein receptor-related protein 6 (LRP6), a requisite coreceptor for ligand-dependent canonical Wnt signaling. Decrease in LRP6 protein seen with calcipotriol was mediated through a novel mechanism involving transcriptional upregulation of low-density lipoprotein receptor adaptor protein 1 (LDLRAP1). Finally, changes in LRP6 or LDLRAP1 expression directly altered Wnt reporter activity, supporting their roles as regulators of ligand-dependent Wnt/β-catenin signaling.This study provides a novel biochemical target through which vitamin D signaling exerts inhibitory effects on Wnt/β-catenin signaling, as well as potential biomarkers for predicting and following tumor response to vitamin D-based therapy.

PubMed ID: 26224368 Exiting the NIEHS site

MeSH Terms: Adaptor Proteins, Signal Transducing/metabolism*; Antineoplastic Agents/pharmacology*; Antineoplastic Agents/therapeutic use; Calcitriol/analogs & derivatives*; Calcitriol/pharmacology; Calcitriol/therapeutic use; Carcinoma, Pancreatic Ductal/metabolism*; Carcinoma, Pancreatic Ductal/pathology; Cell Line, Tumor; Cell Proliferation/drug effects; Humans; Low Density Lipoprotein Receptor-Related Protein-6/metabolism*; Molecular Targeted Therapy; Wnt Signaling Pathway/drug effects*

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