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Inhibition of canonical WNT/β-catenin signaling is involved in leflunomide (LEF)-mediated cytotoxic effects on renal carcinoma cells

Leflunomide (LEF), an inhibitor of dihydroorotate dehydrogenase (DHODH) in pyrimidine biosynthetic pathway, is an immunomodulatory agent approved for the treatment of rheumatoid arthritis. In this study, we show that LEF significantly reduced cell proliferation of renal carcinoma cells in a concentr... Full description

Journal Title: Oncotarget 02 August 2016, Vol.7(31), pp.50401-50416
Main Author: Chen, Yicheng
Other Authors: Huang, Qiaoli , Zhou, Hua , Wang, Yueping , Hu, Xian , Li, Tao
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1949-2553 ; PMID: 27391060 Version:1 ; DOI: 10.18632/oncotarget.10409
Link: http://pubmed.gov/27391060
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recordid: medline27391060
title: Inhibition of canonical WNT/β-catenin signaling is involved in leflunomide (LEF)-mediated cytotoxic effects on renal carcinoma cells
format: Article
creator:
  • Chen, Yicheng
  • Huang, Qiaoli
  • Zhou, Hua
  • Wang, Yueping
  • Hu, Xian
  • Li, Tao
subjects:
  • Wnt/Β-Catenin Signaling
  • Cytotoxicity
  • Leflunomide
  • Renal Cell Carcinoma
  • Carcinoma, Renal Cell -- Drug Therapy
  • Isoxazoles -- Pharmacology
  • Wnt3a Protein -- Metabolism
  • Beta Catenin -- Metabolism
ispartof: Oncotarget, 02 August 2016, Vol.7(31), pp.50401-50416
description: Leflunomide (LEF), an inhibitor of dihydroorotate dehydrogenase (DHODH) in pyrimidine biosynthetic pathway, is an immunomodulatory agent approved for the treatment of rheumatoid arthritis. In this study, we show that LEF significantly reduced cell proliferation of renal carcinoma cells in a concentration-dependent manner. LEF at 50 μM induced S-phase arrest and autophagy. Higher doses of LEF (>50 μM) effectively induced cell apoptosis. Modulating the concentration of LEF resulted in distinct effects on the expression of regulatory proteins associated with cell cycle, apoptosis, and autophagy. In particular, high concentrations of LEF inhibited canonical WNT signaling by promoting nucleo-cytoplasmic shuttling and proteasome-dependent degradation of β-catenin. Mechanistic studies showed that the repression of AKT activation partly accounted for LEF-mediated WNT inhibition. Gene expression microarray revealed that LEF treatment greatly inhibited the expression of FZD10 gene, a receptor mediating WNT/β-catenin activation. In vivo xenograft study in NOD/SCID mice further validated the inhibitory effects of LEF on tumor growth and Wnt/β-catenin signaling. However, LEF treatment also triggered cell autophagy and elevated the expression of WNT3a, which ameliorated its cytotoxic effects. The combination of LEF with a WNT inhibitor IWP-2 or autophagy inhibitor HCQ could yield an enhanced anti-tumor outcome. Taken together, these results identify the potential utility and pharmacological feature of LEF in the chemotherapy of renal cell carcinoma (RCC).
language: eng
source:
identifier: E-ISSN: 1949-2553 ; PMID: 27391060 Version:1 ; DOI: 10.18632/oncotarget.10409
fulltext: fulltext
issn:
  • 19492553
  • 1949-2553
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titleInhibition of canonical WNT/β-catenin signaling is involved in leflunomide (LEF)-mediated cytotoxic effects on renal carcinoma cells
creatorChen, Yicheng ; Huang, Qiaoli ; Zhou, Hua ; Wang, Yueping ; Hu, Xian ; Li, Tao
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subjectWnt/Β-Catenin Signaling ; Cytotoxicity ; Leflunomide ; Renal Cell Carcinoma ; Carcinoma, Renal Cell -- Drug Therapy ; Isoxazoles -- Pharmacology ; Wnt3a Protein -- Metabolism ; Beta Catenin -- Metabolism
descriptionLeflunomide (LEF), an inhibitor of dihydroorotate dehydrogenase (DHODH) in pyrimidine biosynthetic pathway, is an immunomodulatory agent approved for the treatment of rheumatoid arthritis. In this study, we show that LEF significantly reduced cell proliferation of renal carcinoma cells in a concentration-dependent manner. LEF at 50 μM induced S-phase arrest and autophagy. Higher doses of LEF (>50 μM) effectively induced cell apoptosis. Modulating the concentration of LEF resulted in distinct effects on the expression of regulatory proteins associated with cell cycle, apoptosis, and autophagy. In particular, high concentrations of LEF inhibited canonical WNT signaling by promoting nucleo-cytoplasmic shuttling and proteasome-dependent degradation of β-catenin. Mechanistic studies showed that the repression of AKT activation partly accounted for LEF-mediated WNT inhibition. Gene expression microarray revealed that LEF treatment greatly inhibited the expression of FZD10 gene, a receptor mediating WNT/β-catenin activation. In vivo xenograft study in NOD/SCID mice further validated the inhibitory effects of LEF on tumor growth and Wnt/β-catenin signaling. However, LEF treatment also triggered cell autophagy and elevated the expression of WNT3a, which ameliorated its cytotoxic effects. The combination of LEF with a WNT inhibitor IWP-2 or autophagy inhibitor HCQ could yield an enhanced anti-tumor outcome. Taken together, these results identify the potential utility and pharmacological feature of LEF in the chemotherapy of renal cell carcinoma (RCC).
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titleInhibition of canonical WNT/β-catenin signaling is involved in leflunomide (LEF)-mediated cytotoxic effects on renal carcinoma cells
descriptionLeflunomide (LEF), an inhibitor of dihydroorotate dehydrogenase (DHODH) in pyrimidine biosynthetic pathway, is an immunomodulatory agent approved for the treatment of rheumatoid arthritis. In this study, we show that LEF significantly reduced cell proliferation of renal carcinoma cells in a concentration-dependent manner. LEF at 50 μM induced S-phase arrest and autophagy. Higher doses of LEF (>50 μM) effectively induced cell apoptosis. Modulating the concentration of LEF resulted in distinct effects on the expression of regulatory proteins associated with cell cycle, apoptosis, and autophagy. In particular, high concentrations of LEF inhibited canonical WNT signaling by promoting nucleo-cytoplasmic shuttling and proteasome-dependent degradation of β-catenin. Mechanistic studies showed that the repression of AKT activation partly accounted for LEF-mediated WNT inhibition. Gene expression microarray revealed that LEF treatment greatly inhibited the expression of FZD10 gene, a receptor mediating WNT/β-catenin activation. In vivo xenograft study in NOD/SCID mice further validated the inhibitory effects of LEF on tumor growth and Wnt/β-catenin signaling. However, LEF treatment also triggered cell autophagy and elevated the expression of WNT3a, which ameliorated its cytotoxic effects. The combination of LEF with a WNT inhibitor IWP-2 or autophagy inhibitor HCQ could yield an enhanced anti-tumor outcome. Taken together, these results identify the potential utility and pharmacological feature of LEF in the chemotherapy of renal cell carcinoma (RCC).
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abstractLeflunomide (LEF), an inhibitor of dihydroorotate dehydrogenase (DHODH) in pyrimidine biosynthetic pathway, is an immunomodulatory agent approved for the treatment of rheumatoid arthritis. In this study, we show that LEF significantly reduced cell proliferation of renal carcinoma cells in a concentration-dependent manner. LEF at 50 μM induced S-phase arrest and autophagy. Higher doses of LEF (>50 μM) effectively induced cell apoptosis. Modulating the concentration of LEF resulted in distinct effects on the expression of regulatory proteins associated with cell cycle, apoptosis, and autophagy. In particular, high concentrations of LEF inhibited canonical WNT signaling by promoting nucleo-cytoplasmic shuttling and proteasome-dependent degradation of β-catenin. Mechanistic studies showed that the repression of AKT activation partly accounted for LEF-mediated WNT inhibition. Gene expression microarray revealed that LEF treatment greatly inhibited the expression of FZD10 gene, a receptor mediating WNT/β-catenin activation. In vivo xenograft study in NOD/SCID mice further validated the inhibitory effects of LEF on tumor growth and Wnt/β-catenin signaling. However, LEF treatment also triggered cell autophagy and elevated the expression of WNT3a, which ameliorated its cytotoxic effects. The combination of LEF with a WNT inhibitor IWP-2 or autophagy inhibitor HCQ could yield an enhanced anti-tumor outcome. Taken together, these results identify the potential utility and pharmacological feature of LEF in the chemotherapy of renal cell carcinoma (RCC).
doi10.18632/oncotarget.10409
pmid27391060
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date2016-08-02