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.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most common cancer, and second leading cause of cancer deaths worldwide [1], accounting for more than 745,000 deaths annually
Multiple key factors along the WNT/β-catenin signaling cascade represent potential therapeutic targets [27]; here we provide initial evidence to support that the TNKS enzymes are feasible targets with clinical relevance in HCC
We confirmed the predominant over-expression of TNKS1 mRNA and protein levels in human HCC tumors compared to adjacent non-tumor liver tissues, whereas TNKS2 is elevated only at mRNA level
Summary
Hepatocellular carcinoma (HCC) is the sixth most common cancer, and second leading cause of cancer deaths worldwide [1], accounting for more than 745,000 deaths annually. Predominant in sub-Saharan Africa and Asia, its incidence is increasing in the United States, where there are an estimated 33,000 new cases in 2014 [2]. Sorafenib is the only FDA approved, first line therapy for patients with advanced HCC [5]; there is no second line therapy available for patients who do not respond to, or have developed resistance to sorafenib [6]. An increasing number of drug candidates are under preclinical/clinical investigations, many phase III clinical trials reported no significant survival benefit compared to sorafenib [7]. There is an unmet need for more potent targeted or adjuvant therapies to improve current HCC management
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