Oncotarget

Research Papers:

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

Yicheng Chen, Qiaoli Huang, Hua Zhou, Yueping Wang, Xian Hu and Tao Li _

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Oncotarget. 2016; 7:50401-50416. https://doi.org/10.18632/oncotarget.10409

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Abstract

Yicheng Chen1, Qiaoli Huang2, Hua Zhou2, Yueping Wang3, Xian Hu4, Tao Li2

1Department of Urology, Sir Run-Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, China

2Department of Biology, College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua, Zhejiang 321004, China

3Department of Urology, Wuyi First People's Hospital, Wuyi, Zhejiang 321200, China

4Department of Plastic Surgery, Sir Run-Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, China

Correspondence to:

Tao Li, email: litao@zjnu.cn

Keywords: leflunomide, renal cell carcinoma, cytotoxicity, WNT/β-catenin signaling

Received: February 05, 2016     Accepted: June 13, 2016     Published: July 6, 2016

ABSTRACT

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).


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