Evaluation of AXIN1 and AXIN2 as targets of tankyrase inhibition in hepatocellular carcinoma cell lines
Abstract AXIN1 mutations are observed in 8–10% of hepatocellular carcinomas (HCCs) and originally were considered to support tumor growth by aberrantly enhancing β-catenin signaling. This view has however been challenged by reports showing neither a clear nuclear β-catenin accumulation nor clearly e...
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doaj-d777e74f205b42679a788f43c00cff6c2021-04-04T11:29:59ZengNature Publishing GroupScientific Reports2045-23222021-04-0111111310.1038/s41598-021-87091-4Evaluation of AXIN1 and AXIN2 as targets of tankyrase inhibition in hepatocellular carcinoma cell linesWenhui Wang0Pengyu Liu1Marla Lavrijsen2Shan Li3Ruyi Zhang4Shanshan Li5Wesley S. van de Geer6Harmen J. G. van de Werken7Maikel P. Peppelenbosch8Ron Smits9Department of Gastroenterology and Hepatology, Erasmus MC-University Medical CenterDepartment of Gastroenterology and Hepatology, Erasmus MC-University Medical CenterDepartment of Gastroenterology and Hepatology, Erasmus MC-University Medical CenterDepartment of Gastroenterology and Hepatology, Erasmus MC-University Medical CenterDepartment of Gastroenterology and Hepatology, Erasmus MC-University Medical CenterDepartment of Gastroenterology and Hepatology, Erasmus MC-University Medical CenterDepartment of Urology, Erasmus MC Cancer Institute, Erasmus MC-University Medical CenterDepartment of Urology, Erasmus MC Cancer Institute, Erasmus MC-University Medical CenterDepartment of Gastroenterology and Hepatology, Erasmus MC-University Medical CenterDepartment of Gastroenterology and Hepatology, Erasmus MC-University Medical CenterAbstract AXIN1 mutations are observed in 8–10% of hepatocellular carcinomas (HCCs) and originally were considered to support tumor growth by aberrantly enhancing β-catenin signaling. This view has however been challenged by reports showing neither a clear nuclear β-catenin accumulation nor clearly enhanced expression of β-catenin target genes. Here, using nine HCC lines, we show that AXIN1 mutation or siRNA mediated knockdown contributes to enhanced β-catenin signaling in all AXIN1-mutant and non-mutant lines, also confirmed by reduced signaling in AXIN1-repaired SNU449 cells. Both AXIN1 and AXIN2 work synergistically to control β-catenin signaling. While in the AXIN1-mutant lines, AXIN2 is solely responsible for keeping signaling in check, in the non-mutant lines both AXIN proteins contribute to β-catenin regulation to varying levels. The AXIN proteins have gained substantial interest in cancer research for a second reason. Their activity in the β-catenin destruction complex can be increased by tankyrase inhibitors, which thus may serve as a therapeutic option to reduce the growth of β-catenin-dependent cancers. At concentrations that inhibit tankyrase activity, some lines (e.g. HepG2, SNU398) were clearly affected in colony formation, but in most cases apparently independent from effects on β-catenin signaling. Overall, our analyses show that AXIN1 inactivation leads to enhanced β-catenin signaling in HCC cell lines, questioning the strong statements that have been made in this regard. Enhancing AXIN activity by tankyrase monotherapy provides however no effective treatment to affect their growth exclusively through reducing β-catenin signaling.https://doi.org/10.1038/s41598-021-87091-4 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Wenhui Wang Pengyu Liu Marla Lavrijsen Shan Li Ruyi Zhang Shanshan Li Wesley S. van de Geer Harmen J. G. van de Werken Maikel P. Peppelenbosch Ron Smits |
spellingShingle |
Wenhui Wang Pengyu Liu Marla Lavrijsen Shan Li Ruyi Zhang Shanshan Li Wesley S. van de Geer Harmen J. G. van de Werken Maikel P. Peppelenbosch Ron Smits Evaluation of AXIN1 and AXIN2 as targets of tankyrase inhibition in hepatocellular carcinoma cell lines Scientific Reports |
author_facet |
Wenhui Wang Pengyu Liu Marla Lavrijsen Shan Li Ruyi Zhang Shanshan Li Wesley S. van de Geer Harmen J. G. van de Werken Maikel P. Peppelenbosch Ron Smits |
author_sort |
Wenhui Wang |
title |
Evaluation of AXIN1 and AXIN2 as targets of tankyrase inhibition in hepatocellular carcinoma cell lines |
title_short |
Evaluation of AXIN1 and AXIN2 as targets of tankyrase inhibition in hepatocellular carcinoma cell lines |
title_full |
Evaluation of AXIN1 and AXIN2 as targets of tankyrase inhibition in hepatocellular carcinoma cell lines |
title_fullStr |
Evaluation of AXIN1 and AXIN2 as targets of tankyrase inhibition in hepatocellular carcinoma cell lines |
title_full_unstemmed |
Evaluation of AXIN1 and AXIN2 as targets of tankyrase inhibition in hepatocellular carcinoma cell lines |
title_sort |
evaluation of axin1 and axin2 as targets of tankyrase inhibition in hepatocellular carcinoma cell lines |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2021-04-01 |
description |
Abstract AXIN1 mutations are observed in 8–10% of hepatocellular carcinomas (HCCs) and originally were considered to support tumor growth by aberrantly enhancing β-catenin signaling. This view has however been challenged by reports showing neither a clear nuclear β-catenin accumulation nor clearly enhanced expression of β-catenin target genes. Here, using nine HCC lines, we show that AXIN1 mutation or siRNA mediated knockdown contributes to enhanced β-catenin signaling in all AXIN1-mutant and non-mutant lines, also confirmed by reduced signaling in AXIN1-repaired SNU449 cells. Both AXIN1 and AXIN2 work synergistically to control β-catenin signaling. While in the AXIN1-mutant lines, AXIN2 is solely responsible for keeping signaling in check, in the non-mutant lines both AXIN proteins contribute to β-catenin regulation to varying levels. The AXIN proteins have gained substantial interest in cancer research for a second reason. Their activity in the β-catenin destruction complex can be increased by tankyrase inhibitors, which thus may serve as a therapeutic option to reduce the growth of β-catenin-dependent cancers. At concentrations that inhibit tankyrase activity, some lines (e.g. HepG2, SNU398) were clearly affected in colony formation, but in most cases apparently independent from effects on β-catenin signaling. Overall, our analyses show that AXIN1 inactivation leads to enhanced β-catenin signaling in HCC cell lines, questioning the strong statements that have been made in this regard. Enhancing AXIN activity by tankyrase monotherapy provides however no effective treatment to affect their growth exclusively through reducing β-catenin signaling. |
url |
https://doi.org/10.1038/s41598-021-87091-4 |
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