1. Academic Validation
  2. The anthelmintic drug niclosamide induces GSK-β-mediated β-catenin degradation to potentiate gemcitabine activity, reduce immune evasion ability and suppress pancreatic cancer progression

The anthelmintic drug niclosamide induces GSK-β-mediated β-catenin degradation to potentiate gemcitabine activity, reduce immune evasion ability and suppress pancreatic cancer progression

  • Cell Death Dis. 2022 Feb 3;13(2):112. doi: 10.1038/s41419-022-04573-7.
Yangyang Guo  # 1 Hengyue Zhu  # 1 2 Yanyi Xiao 1 Hangcheng Guo 1 Miaomiao Lin 1 3 Ziwei Yuan 1 Xuejia Yang 1 Youze Huang 4 Qiyu Zhang 5 Yongheng Bai 6 7
Affiliations

Affiliations

  • 1 Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
  • 2 Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
  • 3 Human Genetic Resource Bank, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
  • 4 Department of Laboratory Medicine, Wenzhou Hospital of Traditional Chinese Medicine, Wenzhou, 325000, China.
  • 5 Department for Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China. zhangqiyu@hosp1.ac.cn.
  • 6 Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China. wzbyh@wmu.edu.cn.
  • 7 Center for Health Assessment, Wenzhou Medical University, Wenzhou, 325000, China. wzbyh@wmu.edu.cn.
  • # Contributed equally.
Abstract

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 β-catenin. Niclosamide did not reduce β-catenin mRNA expression in PCCs, but significantly downregulated its protein level. Moreover, niclosamide induced β-catenin phosphorylation and protein degradation. Interestingly, niclosamide also induced GSK-3β phosphorylation, which is involved in the ubiquitination degradation of β-catenin. Pharmacological activation of β-catenin by methyl vanillate and β-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-β-mediated β-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.

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