American Association for Cancer Research
15417786mcr150204-sup-148285_1_supp_3044180_nqvhz5.xlsx (190.34 kB)

Supplemental Table 2 from Calcipotriol Targets LRP6 to Inhibit Wnt Signaling in Pancreatic Cancer

Download (190.34 kB)
posted on 2023-04-03, 17:09 authored by 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

Supplemental Table 2. RNA-Seq analysis showing significant gene expression changes following 6 hour calcipotriol treatment of AsPC-1 cell line



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.Implications: 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. Mol Cancer Res; 13(11); 1509–19. ©2015 AACR.