Calcipotriol targets LRP6 to inhibit wnt signaling in pancreatic cancer

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

Research output: Contribution to journalArticle

21 Scopus citations

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 liganddependent Wnt/β-catenin signaling. Implications: This study provides a novel biochemical target through which vitamin D signaling exerts inhibitory effects on Wnt/fS-catenin signaling, as well as potential biomarkers for predicting and following tumor response to vitamin D-based therapy.

Original languageEnglish (US)
Pages (from-to)1509-1519
Number of pages11
JournalMolecular Cancer Research
Volume13
Issue number11
DOIs
StatePublished - Nov 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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    Arensman, M. D., Nguyen, P., Kershaw, K. M., Lay, A. R., Ostertag-Hill, C. A., Sherman, M. H., Downes, M., Liddle, C., Evans, R. M., & Dawson, D. W. (2015). Calcipotriol targets LRP6 to inhibit wnt signaling in pancreatic cancer. Molecular Cancer Research, 13(11), 1509-1519. https://doi.org/10.1158/1541-7786.MCR-15-0204