Abstract B77: Vitamin D suppresses pancreatic cancer growth through inhibition of autocrine Wnt/β-catenin signaling

Abstract

Abstract Epidemiological studies indicate higher vitamin D levels are associated with a reduced risk for pancreatic ductal adenocarcinoma (PDAC) and other malignancies. Although vitamin D analogs inhibit the growth of some PDAC cell lines in vitro and in vivo, a clinical trial with an active metabolite of vitamin D (seocalcitol) demonstrated no objective response in patients with inoperable PDAC. In addition to initiating vitamin D receptor (VDR) mediated transcription, vitamin D is known to inhibit Wnt/β-catenin signaling, a pathway recently shown to play a critical role in pancreatic cancer initiation and progression. For this study we chose to explore a possible link between these two signaling pathways. Initially, we found VDR expression strongly correlated with endogenous Wnt/β-catenin signaling activity across a large panel of PDAC cell lines, suggesting VDR may serve as a critical mediator of Wnt/β-catenin signaling in PDAC and/or that VDR itself may be a transcriptional target of the Wnt pathway. Therefore, we next determined whether the growth inhibitory effects of vitamin D analog calcipotriol in PDAC cell lines could be mechanistically linked to its action on Wnt/β-catenin signaling. Using a β-catenin-activated reporter, we found calcipotriol inhibited Wnt/β-catenin signaling and anchorage-dependent growth in a dose-dependent manner and with greater efficacy in those PDAC cell lines with high levels of endogenous Wnt/β-catenin signaling (Wnt high). In parallel, calcipotriol also inhibited anchorage-independent growth of the same Wnt high PDAC lines in soft agar assays, a phenotype we have previously shown to be critically linked to autocrine Wnt/β-catenin signaling activity. Previously published work in colorectal cancer finds vitamin D initiates a physical interaction between VDR and β-catenin that translocates β-catenin from the nucleus to the plasma membrane to inhibit Wnt/β-catenin mediated transcription. However, in exploring this potential biochemical interaction in PDAC cell lines we have been unable to co-immunoprecipitate VDR and β-catenin, leading us to speculate that vitamin D disrupts Wnt/β-catenin signaling through a novel alternative mechanism that we are currently investigating. In conclusion, the present study identifies a subset of PDAC cell lines defined by higher levels of Wnt/β-catenin signaling that show increased sensitivity to vitamin D-mediated growth inhibition. These results may be of clinical utility in stratifying patients most likely to benefit from vitamin D-based therapy. Citation Format: Michael Dawson Arensman, Claire Ostertag-Hill, Anna Rose Lay, David Dawson. Vitamin D suppresses pancreatic cancer growth through inhibition of autocrine Wnt/β-catenin signaling. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B77.