Wnt/β-Catenin Signaling: The Culprit in Pancreatic Carcinogenesis and Therapeutic Resistance

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is responsible for 7.3% of all cancer deaths. Even though there is a steady increase in patient survival for most cancers over the decades, the patient survival rate for pancreatic cancer remains low with current therapeutic strategies. The Wnt/β-catenin pathway controls the maintenance of somatic stem cells in many tissues and organs and is implicated in pancreatic carcinogenesis by regulating cell cycle progression, apoptosis, epithelial-mesenchymal transition (EMT), angiogenesis, stemness, tumor immune microenvironment, etc. Further, dysregulated Wnt has been shown to cause drug resistance in pancreatic cancer. Although different Wnt antagonists are effective in pancreatic patients, limitations remain that must be overcome to increase the survival benefits associated with this emerging therapy. In this review, we have summarized the role of Wnt signaling in pancreatic cancer and suggested future directions to enhance the survival of pancreatic cancer patients.

Astragalus polysaccharide inhibits breast cancer cell migration and invasion by regulating epithelial‑mesenchymal transition via the Wnt/β‑catenin signaling pathway

“…cyclin d1and c-Myc are downstream factors of the Wnt/β-catenin signaling pathway (18). The mrna expression of c-Myc was significantly decreased in McF-7 and Mda-MB-231 cells treated with 400 and 800 µg/ml aPS cells compared with the control group (Fig.…”

“…The accumulation of β-catenin in the cytoplasm and its translocation into the nucleus are critical for the activation of β-catenin target gene transcription (18). Treatment with aPS (400 and 800 µg/ml) significantly decreased the protein expression level of cytoplasmic and nuclear β-catenin compared with the control group (Fig.…”

“…However, in the non-canonical pathway, Wnt proteins can trigger other effectors, including JnK (64)(65)(66). Wnt1 is one of the activators of the Wnt/β-catenin pathway (18). Following activation by Wnt1, β-catenin translocates to the nucleus to regulate the transcription of downstream genes, including Snail, vimentin and e-cadherin (57).…”

“…among these inducers, the Wnt/β-catenin signaling pathway, which can be divided into classical and non-classical signaling pathways, has attracted increasing attention (17). Wnt has been identified as the promoter of the pathway (18) and, as an upstream factor, β-catenin affects the expression of downstream factors of the signaling pathway, including c-Myc and cyclin d1 (19). Previous studies have suggested that the Wnt/β-catenin signaling pathway can influence developmental embryonic processes, determine cell polarity and regulate cell proliferation (20)(21)(22)(23).…”

Cellular Plasticity in Breast Cancer Progression and Therapy

“…Wnt pathway inhibitors have been an area of active investigation for many years, but have often proven difficult to use due to associated toxicities (particularly affecting the GI tract). Currently, Vantictumab, a first-in-class antibody that inhibits canonical Wnt signaling by blocking five Frizzled receptors (1, 2, 5, 7, 8) (Ram Makena et al, 2019) is being used in combination with paclitaxel in phase 1b clinical studies in patients with metastatic HER2-negative breast cancer (Mita et al, 2016). WNT5A is a WNT inhibitory ligand, and Foxy-5, a WNT5A mimicking peptide, has been shown to reduce metastatic spread of WNT5A-low breast cancer cells in mouse models (Safholm et al, 2008;Canesin et al, 2017).…”