Oncotarget

Research Papers:

Tankyrase inhibitors attenuate WNT/β-catenin signaling and inhibit growth of hepatocellular carcinoma cells

Li Ma, Xiaolin Wang, Tao Jia, Wei Wei, Mei-Sze Chua _ and Samuel So

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Oncotarget. 2015; 6:25390-25401. https://doi.org/10.18632/oncotarget.4455

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Abstract

Li Ma1, Xiaolin Wang1,3, Tao Jia2, Wei Wei1, Mei-Sze Chua1, Samuel So1

1Asian Liver Center and Department of Surgery, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA

2School of Pharmaceutical Sciences, Wuhan University, Wuhan, Hubei, 430072, China

3Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510655, China

Correspondence to:

Mei-Sze Chua, e-mail: [email protected]

Keywords: WNT/β-catenin signaling, hepatocellular carcinoma, tankyrase inhibitors, β-catenin/TCF complexes, targeted therapy

Received: March 20, 2015     Accepted: June 15, 2015     Published: June 27, 2015

ABSTRACT

Deregulated WNT/β-catenin signaling contributes to the development of a subgroup of hepatocellular carcinoma (HCC), the second leading cause of cancer deaths worldwide. Within this pathway, the tankyrase enzymes (TNKS1 and TNKS2) degrade AXIN and thereby enhance β-catenin activity. We evaluate TNKS enzymes as potential therapeutic targets in HCC, and the anti-tumor efficacy of tankyrase inhibitors (XAV939, and its novel nitro-substituted derivative WXL-8) in HCC cells. Using semi-quantitative RT-PCR, we found significantly elevated levels of TNKS1/2 mRNA in tumor liver tissues compared to adjacent non-tumor livers, at protein levels only TNKS1 is increased. In HepG2, Huh7cells, siRNA-mediated knockdown suppression of endogenous TNKS1 and TNKS2 reduced cell proliferation, together with decreased nuclear β-catenin levels. XAV939 and WXL-8 inhibited cell proliferation and colony formation in HepG2, Huh7, and Hep40 cells (p < 0.05), with stabilization of AXIN1 and AXIN2, and decreased β-catenin protein levels. XAV939 and WXL-8 also attenuated rhWNT3A-induced TOPflash luciferase reporter activity in HCC cells, indicating reduced β-catenin transcriptional activity, consistent with decreased nuclear β-catenin levels. In vivo, intra-tumor injections of XAV939 or WXL-8 significantly inhibited the growth of subcutaneous HepG2 xenografts (P < 0.05). We suggest that tankyrase inhibition is a potential therapeutic approach for treating a subgroup HCC with aberrant WNT/β-catenin signaling pathway.


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