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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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d777e74f205b42679a788f43c00cff6c
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spelling	oai:doaj.org-article:d777e74f205b42679a788f43c00cff6c2021-12-02T14:24:55ZEvaluation of AXIN1 and AXIN2 as targets of tankyrase inhibition in hepatocellular carcinoma cell lines10.1038/s41598-021-87091-42045-2322https://doaj.org/article/d777e74f205b42679a788f43c00cff6c2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87091-4https://doaj.org/toc/2045-2322Abstract 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.Wenhui WangPengyu LiuMarla LavrijsenShan LiRuyi ZhangShanshan LiWesley S. van de GeerHarmen J. G. van de WerkenMaikel P. PeppelenboschRon SmitsNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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.
format	article
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
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 Portfolio
publishDate	2021
url	https://doaj.org/article/d777e74f205b42679a788f43c00cff6c
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Evaluation of AXIN1 and AXIN2 as targets of tankyrase inhibition in hepatocellular carcinoma cell lines

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