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

ABSTRACT: Deregulated WNT/?-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 ?-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 ?-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 ?-catenin protein levels. XAV939 and WXL-8 also attenuated rhWNT3A-induced TOPflash luciferase reporter activity in HCC cells, indicating reduced ?-catenin transcriptional activity, consistent with decreased nuclear ?-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/?-catenin signaling pathway.

SUBMITTER: Ma L

PROVIDER: S-EPMC4694839 | biostudies-other | 2015 Sep

REPOSITORIES: biostudies-other

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

Ma Li L Wang Xiaolin X Jia Tao T Wei Wei W Chua Mei-Sze MS So Samuel S

Oncotarget 20150901 28

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 ...[more]

PMID: 26246473

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Project description:BackgroundHepatocellular carcinoma is a widespread cancer worldwide, ranking as the fifth most frequent cancer and the fourth leading cause of cancer-related deaths. According to comprehensive research, TLK2, a phosphorylated kinase, has been discovered to play a crucial role in promoting tumor development. However, the prognostic significance and influence of TLK2 on hepatocellular carcinoma tumor cells and the immune microenvironment remain unexplored, warranting further investigation. The aim of this study was to investigate the role of TLK2 in promoting the development of hepatocellular carcinoma.MethodsThe present study utilized The Cancer Genome Atlas (TCGA) database and other databases as training sets to examine the expression of TLK2 and its prognostic significance. The findings were subsequently validated through cell proliferation assays and cell colony assays. Gene set enrichment analysis (GSEA) was employed to investigate the tumor-related biological processes associated with TLK2 in hepatocellular carcinoma, while the relationship between TLK2 expression and Wnt/β-catenin signaling pathway was analyzed via TCGA dataset analysis. Western blotting and immunofluorescence assays were used to confirm the experimental results.ResultsTLK2 showed higher expression levels in tumor tissues than in normal tissues. Alpha fetoprotein (AFP), T stage, pathological stage, and histological grade were significantly associated with TLK2 expression. High TLK2 expression correlated with worse overall survival (OS) [hazard ratio (HR) =1.62, 95% confidence interval (CI): 1.14-2.29, P=0.007], progression-free survival (PFS) (HR =1.88, 95% CI: 1.40-2.52, P<0.001) and disease specific survival (DSS) (HR =1.86, 95% CI: 1.18-2.93, P=0.007) in the training and validation sets. Both univariate and multivariate analyses showed that TLK2 was an independent prognostic factor. GSEA showed that TLK2 was significantly enriched in tumor-related biological processes. TLK2 induced the activation of β-catenin signaling, resulting in sustained tumor growth. Methyl thiazolyl tetrazolium (MTT) and colony formation assays demonstrated that TLK2 could promote hepatocellular carcinoma progression. Furthermore, TLK2 showed a significant association with β-catenin in the Wnt pathway.ConclusionsTLK2 represents an independent prognostic factor in hepatocellular carcinoma and can promote cancer progression via the β-catenin signaling pathway.

Dataset Information

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

Publications

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

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