The anthelmintic drug niclosamide induces GSK-beta-mediated beta-catenin degradation to potentiate gemcitabine activity, reduce immune evasion ability and suppress pancreatic cancer progression (vol 13, 112, 2022)

Niclosamide, a cell-permeable salicylanilide, was approved by the Food and Drug Administration for its anthelmintic efficiency. A growing body of evidence in recent years suggests that niclosamide exhibits potential tumor-suppressive activity. However, the role and molecular mechanism of niclosamide in pancreatic cancer remain unclear. In this study, niclosamide inhibited proliferation of pancreatic cancer cells (PCCs), induced apoptosis via the mitochondrial-mediated pathway, and suppressed cell migration and invasion by antagonizing epithelial-to-mesenchymal transition. Also, niclosamide inhibited tumor growth and metastasis in pancreatic cancer xenograft mouse models. Mechanistically, niclosamide exerted these therapeutic effects via targeting beta-catenin. Niclosamide did not reduce beta-catenin mRNA expression in PCCs, but significantly downregulated its protein level. Moreover, niclosamide induced beta-catenin phosphorylation and protein degradation. Interestingly, niclosamide also induced GSK-3 beta phosphorylation, which is involved in the ubiquitination degradation of beta-catenin. Pharmacological activation of beta-catenin by methyl vanillate and beta-catenin overexpression abolished the inhibitory effects of niclosamide. Furthermore, niclosamide potentiated the antitumor effect of the chemotherapy drug gemcitabine and reduced the ability of cancer immune evasion by downregulating the expression levels of PD-L1, which is involved in T cell immunity. Thus, our study indicated that niclosamide induces GSK-beta-mediated beta-catenin degradation to potentiate gemcitabine activity, reduce immune evasion ability, and suppress pancreatic cancer progression. Niclosamide may be a potential therapeutic candidate for pancreatic cancer.