Calcipotriol Targets LRP6 to Inhibit Wnt Signaling in Pancreatic Cancer

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 biological activity is vitamin D, which is known to antagonize Wnt/β-catenin signaling in colorectal cancer and have anti-tumor 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 analog. PDAC tumor cell growth inhibition by calcipotriol was positively correlated with vitamin D receptor (VDR) 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 co-receptor 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.

DKK1 Induced by 1,25D3 Is Required for the Mineralization of Osteoblasts

“…1,25D3 exerts its actions via binding with and modulating the vitamin D receptor (VDR), a transcriptional regulator [11][12][13]. 1,25D3 also activates Wnt/β-catenin to facilitate osteoblast differentiation [14][15][16]. Conversely, 1,25D3 induces Dickkopf-1 (DKK1) transcripts to suppress Wnt/β-catenin in bladder and colon cancers [17,18], suggesting that 1,25D3 has tissue-specific effects on Wnt/β-catenin signaling.…”

Prediagnostic Plasma 25-Hydroxyvitamin D and Pancreatic Cancer Survival

“…[3][4][5] Recent studies in laboratory models of pancreatic cancer have demonstrated the therapeutic potential of vitamin D analogs by engagement of VDR in tumor cells and supportive cells within the tumor stroma. [6][7][8] Although studies that have evaluated circulating vitamin D and pancreatic cancer incidence have been conflicting, 9,10 few studies have been conducted to assess the association of vitamin D levels with survival in patients with pancreatic cancer. 11,12 To assess the potential prognostic effect of vitamin D status, we evaluated the association between prediagnostic plasma 25-hydroxyvitamin D [25(OH)D] and overall survival among patients with pancreatic cancer drawn from five large US prospective cohorts.…”

miR-202-3p Regulates Sertoli Cell Proliferation, Synthesis Function, and Apoptosis by Targeting LRP6 and Cyclin D1 of Wnt/β-Catenin Signaling

“…Overexpression of LRP6 contributes to the hyperactivation of the Wnt/β-catenin signaling pathway, which could promote the progression and invasion of various tumors, including hepatocellular carcinomas, colorectal cancer, prostate cancer, breast cancer, and pancreatic cancer. 59 , 74 , 75 Aberrant function of LRP6 is also related to many other diseases, such as autosomal-dominant oligodontia, Alzheimer’s disease, atherosclerosis, and diabetic retinopathy. In the male reproductive system, Wnt/β-catenin signaling plays important roles in the differentiation of Müllerian duct, organization of testicular cords, development of primordial germ cells, and proliferation and differentiation of spermatogonia.…”