Cargando…

Beta-Hydroxyisovaleryl-Shikonin Eradicates Epithelial Cell Adhesion Molecule-Positive Liver Cancer Stem Cells by Suppressing dUTP Pyrophosphatase Expression

Cancer stem cells (CSCs) play an essential role in tumorigenesis, chemoresistance, and metastasis. Previously, we demonstrated that the development of hepatocellular carcinoma (HCC) is dictated by a subset of epithelial cell adhesion molecule-positive (EpCAM+) liver CSCs with the activation of Wnt s...

Descripción completa

Detalles Bibliográficos
Autores principales: Asahina, Yoshiro, Takatori, Hajime, Nio, Kouki, Okada, Hikari, Hayashi, Takehiro, Hayashi, Tomoyuki, Hashiba, Tomomi, Suda, Tsuyoshi, Nishitani, Masaki, Sugimoto, Saiho, Honda, Masao, Kaneko, Shuichi, Yamashita, Taro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10671815/
https://www.ncbi.nlm.nih.gov/pubmed/38003473
http://dx.doi.org/10.3390/ijms242216283
_version_ 1785149462116564992
author Asahina, Yoshiro
Takatori, Hajime
Nio, Kouki
Okada, Hikari
Hayashi, Takehiro
Hayashi, Tomoyuki
Hashiba, Tomomi
Suda, Tsuyoshi
Nishitani, Masaki
Sugimoto, Saiho
Honda, Masao
Kaneko, Shuichi
Yamashita, Taro
author_facet Asahina, Yoshiro
Takatori, Hajime
Nio, Kouki
Okada, Hikari
Hayashi, Takehiro
Hayashi, Tomoyuki
Hashiba, Tomomi
Suda, Tsuyoshi
Nishitani, Masaki
Sugimoto, Saiho
Honda, Masao
Kaneko, Shuichi
Yamashita, Taro
author_sort Asahina, Yoshiro
collection PubMed
description Cancer stem cells (CSCs) play an essential role in tumorigenesis, chemoresistance, and metastasis. Previously, we demonstrated that the development of hepatocellular carcinoma (HCC) is dictated by a subset of epithelial cell adhesion molecule-positive (EpCAM+) liver CSCs with the activation of Wnt signaling. In this study, we evaluated the expression of dUTP pyrophosphatase (dUTPase), which plays a central role in the development of chemoresistance to 5-fluorouracil, in EpCAM+ HCC cells. We further evaluated the effect of beta-hydroxyisovaleryl-shikonin (β-HIVS), an ATP-noncompetitive inhibitor of protein tyrosine kinases, on HCC CSCs. EpCAM and dUTPase were expressed in hepatoblasts in human fetal liver, hepatic progenitors in adult cirrhotic liver, and a subset of HCC cells. Sorted EpCAM+ CSCs from HCC cell lines showed abundant nuclear accumulation of dUTPase compared with EpCAM-negative cells. Furthermore, treatment with the Wnt signaling activator BIO increased EpCAM and dUTPase expression. In contrast, β-HIVS treatment decreased dUTPase expression. β-HIVS treatment decreased the population of EpCAM+ liver CSCs in a dose-dependent manner in vitro and suppressed tumor growth in vivo compared with the control vehicle. Taken together, our data suggest that dUTPase could be a good target to eradicate liver CSCs resistant to 5-fluorouracil. β-HIVS is a small molecule that could decrease dUTPase expression and target EpCAM+ liver CSCs.
format Online
Article
Text
id pubmed-10671815
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-106718152023-11-14 Beta-Hydroxyisovaleryl-Shikonin Eradicates Epithelial Cell Adhesion Molecule-Positive Liver Cancer Stem Cells by Suppressing dUTP Pyrophosphatase Expression Asahina, Yoshiro Takatori, Hajime Nio, Kouki Okada, Hikari Hayashi, Takehiro Hayashi, Tomoyuki Hashiba, Tomomi Suda, Tsuyoshi Nishitani, Masaki Sugimoto, Saiho Honda, Masao Kaneko, Shuichi Yamashita, Taro Int J Mol Sci Article Cancer stem cells (CSCs) play an essential role in tumorigenesis, chemoresistance, and metastasis. Previously, we demonstrated that the development of hepatocellular carcinoma (HCC) is dictated by a subset of epithelial cell adhesion molecule-positive (EpCAM+) liver CSCs with the activation of Wnt signaling. In this study, we evaluated the expression of dUTP pyrophosphatase (dUTPase), which plays a central role in the development of chemoresistance to 5-fluorouracil, in EpCAM+ HCC cells. We further evaluated the effect of beta-hydroxyisovaleryl-shikonin (β-HIVS), an ATP-noncompetitive inhibitor of protein tyrosine kinases, on HCC CSCs. EpCAM and dUTPase were expressed in hepatoblasts in human fetal liver, hepatic progenitors in adult cirrhotic liver, and a subset of HCC cells. Sorted EpCAM+ CSCs from HCC cell lines showed abundant nuclear accumulation of dUTPase compared with EpCAM-negative cells. Furthermore, treatment with the Wnt signaling activator BIO increased EpCAM and dUTPase expression. In contrast, β-HIVS treatment decreased dUTPase expression. β-HIVS treatment decreased the population of EpCAM+ liver CSCs in a dose-dependent manner in vitro and suppressed tumor growth in vivo compared with the control vehicle. Taken together, our data suggest that dUTPase could be a good target to eradicate liver CSCs resistant to 5-fluorouracil. β-HIVS is a small molecule that could decrease dUTPase expression and target EpCAM+ liver CSCs. MDPI 2023-11-14 /pmc/articles/PMC10671815/ /pubmed/38003473 http://dx.doi.org/10.3390/ijms242216283 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Asahina, Yoshiro
Takatori, Hajime
Nio, Kouki
Okada, Hikari
Hayashi, Takehiro
Hayashi, Tomoyuki
Hashiba, Tomomi
Suda, Tsuyoshi
Nishitani, Masaki
Sugimoto, Saiho
Honda, Masao
Kaneko, Shuichi
Yamashita, Taro
Beta-Hydroxyisovaleryl-Shikonin Eradicates Epithelial Cell Adhesion Molecule-Positive Liver Cancer Stem Cells by Suppressing dUTP Pyrophosphatase Expression
title Beta-Hydroxyisovaleryl-Shikonin Eradicates Epithelial Cell Adhesion Molecule-Positive Liver Cancer Stem Cells by Suppressing dUTP Pyrophosphatase Expression
title_full Beta-Hydroxyisovaleryl-Shikonin Eradicates Epithelial Cell Adhesion Molecule-Positive Liver Cancer Stem Cells by Suppressing dUTP Pyrophosphatase Expression
title_fullStr Beta-Hydroxyisovaleryl-Shikonin Eradicates Epithelial Cell Adhesion Molecule-Positive Liver Cancer Stem Cells by Suppressing dUTP Pyrophosphatase Expression
title_full_unstemmed Beta-Hydroxyisovaleryl-Shikonin Eradicates Epithelial Cell Adhesion Molecule-Positive Liver Cancer Stem Cells by Suppressing dUTP Pyrophosphatase Expression
title_short Beta-Hydroxyisovaleryl-Shikonin Eradicates Epithelial Cell Adhesion Molecule-Positive Liver Cancer Stem Cells by Suppressing dUTP Pyrophosphatase Expression
title_sort beta-hydroxyisovaleryl-shikonin eradicates epithelial cell adhesion molecule-positive liver cancer stem cells by suppressing dutp pyrophosphatase expression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10671815/
https://www.ncbi.nlm.nih.gov/pubmed/38003473
http://dx.doi.org/10.3390/ijms242216283
work_keys_str_mv AT asahinayoshiro betahydroxyisovalerylshikonineradicatesepithelialcelladhesionmoleculepositivelivercancerstemcellsbysuppressingdutppyrophosphataseexpression
AT takatorihajime betahydroxyisovalerylshikonineradicatesepithelialcelladhesionmoleculepositivelivercancerstemcellsbysuppressingdutppyrophosphataseexpression
AT niokouki betahydroxyisovalerylshikonineradicatesepithelialcelladhesionmoleculepositivelivercancerstemcellsbysuppressingdutppyrophosphataseexpression
AT okadahikari betahydroxyisovalerylshikonineradicatesepithelialcelladhesionmoleculepositivelivercancerstemcellsbysuppressingdutppyrophosphataseexpression
AT hayashitakehiro betahydroxyisovalerylshikonineradicatesepithelialcelladhesionmoleculepositivelivercancerstemcellsbysuppressingdutppyrophosphataseexpression
AT hayashitomoyuki betahydroxyisovalerylshikonineradicatesepithelialcelladhesionmoleculepositivelivercancerstemcellsbysuppressingdutppyrophosphataseexpression
AT hashibatomomi betahydroxyisovalerylshikonineradicatesepithelialcelladhesionmoleculepositivelivercancerstemcellsbysuppressingdutppyrophosphataseexpression
AT sudatsuyoshi betahydroxyisovalerylshikonineradicatesepithelialcelladhesionmoleculepositivelivercancerstemcellsbysuppressingdutppyrophosphataseexpression
AT nishitanimasaki betahydroxyisovalerylshikonineradicatesepithelialcelladhesionmoleculepositivelivercancerstemcellsbysuppressingdutppyrophosphataseexpression
AT sugimotosaiho betahydroxyisovalerylshikonineradicatesepithelialcelladhesionmoleculepositivelivercancerstemcellsbysuppressingdutppyrophosphataseexpression
AT hondamasao betahydroxyisovalerylshikonineradicatesepithelialcelladhesionmoleculepositivelivercancerstemcellsbysuppressingdutppyrophosphataseexpression
AT kanekoshuichi betahydroxyisovalerylshikonineradicatesepithelialcelladhesionmoleculepositivelivercancerstemcellsbysuppressingdutppyrophosphataseexpression
AT yamashitataro betahydroxyisovalerylshikonineradicatesepithelialcelladhesionmoleculepositivelivercancerstemcellsbysuppressingdutppyrophosphataseexpression