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Disulfiram Eradicates Tumor-Initiating Hepatocellular Carcinoma Cells in ROS-p38 MAPK Pathway-Dependent and -Independent Manners
Tumor-initiating cells (TICs) play a central role in tumor development, metastasis, and recurrence. In the present study, we investigated the effect of disulfiram (DSF), an inhibitor of aldehyde dehydrogenase, toward tumor-initiating hepatocellular carcinoma (HCC) cells. DSF treatment suppressed the...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3890271/ https://www.ncbi.nlm.nih.gov/pubmed/24454751 http://dx.doi.org/10.1371/journal.pone.0084807 |
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author | Chiba, Tetsuhiro Suzuki, Eiichiro Yuki, Kaori Zen, Yoh Oshima, Motohiko Miyagi, Satoru Saraya, Atsunori Koide, Shuhei Motoyama, Tenyu Ogasawara, Sadahisa Ooka, Yoshihiko Tawada, Akinobu Nakatsura, Tetsuya Hayashi, Takehiro Yamashita, Taro Kaneko, Syuichi Miyazaki, Masaru Iwama, Atsushi Yokosuka, Osamu |
author_facet | Chiba, Tetsuhiro Suzuki, Eiichiro Yuki, Kaori Zen, Yoh Oshima, Motohiko Miyagi, Satoru Saraya, Atsunori Koide, Shuhei Motoyama, Tenyu Ogasawara, Sadahisa Ooka, Yoshihiko Tawada, Akinobu Nakatsura, Tetsuya Hayashi, Takehiro Yamashita, Taro Kaneko, Syuichi Miyazaki, Masaru Iwama, Atsushi Yokosuka, Osamu |
author_sort | Chiba, Tetsuhiro |
collection | PubMed |
description | Tumor-initiating cells (TICs) play a central role in tumor development, metastasis, and recurrence. In the present study, we investigated the effect of disulfiram (DSF), an inhibitor of aldehyde dehydrogenase, toward tumor-initiating hepatocellular carcinoma (HCC) cells. DSF treatment suppressed the anchorage-independent sphere formation of both HCC cells. Flow cytometric analyses showed that DSF but not 5-fluorouracil (5-FU) drastically reduces the number of tumor-initiating HCC cells. The sphere formation assays of epithelial cell adhesion molecule (EpCAM)(+) HCC cells co-treated with p38-specific inhibitor revealed that DSF suppresses self-renewal capability mainly through the activation of reactive oxygen species (ROS)-p38 MAPK pathway. Microarray experiments also revealed the enrichment of the gene set involved in p38 MAPK signaling in EpCAM(+) cells treated with DSF but not 5-FU. In addition, DSF appeared to downregulate Glypican 3 (GPC3) in a manner independent of ROS-p38 MAPK pathway. GPC3 was co-expressed with EpCAM in HCC cell lines and primary HCC cells and GPC3-knockdown reduced the number of EpCAM(+) cells by compromising their self-renewal capability and inducing the apoptosis. These results indicate that DSF impaired the tumorigenicity of tumor-initiating HCC cells through activation of ROS-p38 pathway and in part through the downregulation of GPC3. DSF might be a promising therapeutic agent for the eradication of tumor-initiating HCC cells. |
format | Online Article Text |
id | pubmed-3890271 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-38902712014-01-21 Disulfiram Eradicates Tumor-Initiating Hepatocellular Carcinoma Cells in ROS-p38 MAPK Pathway-Dependent and -Independent Manners Chiba, Tetsuhiro Suzuki, Eiichiro Yuki, Kaori Zen, Yoh Oshima, Motohiko Miyagi, Satoru Saraya, Atsunori Koide, Shuhei Motoyama, Tenyu Ogasawara, Sadahisa Ooka, Yoshihiko Tawada, Akinobu Nakatsura, Tetsuya Hayashi, Takehiro Yamashita, Taro Kaneko, Syuichi Miyazaki, Masaru Iwama, Atsushi Yokosuka, Osamu PLoS One Research Article Tumor-initiating cells (TICs) play a central role in tumor development, metastasis, and recurrence. In the present study, we investigated the effect of disulfiram (DSF), an inhibitor of aldehyde dehydrogenase, toward tumor-initiating hepatocellular carcinoma (HCC) cells. DSF treatment suppressed the anchorage-independent sphere formation of both HCC cells. Flow cytometric analyses showed that DSF but not 5-fluorouracil (5-FU) drastically reduces the number of tumor-initiating HCC cells. The sphere formation assays of epithelial cell adhesion molecule (EpCAM)(+) HCC cells co-treated with p38-specific inhibitor revealed that DSF suppresses self-renewal capability mainly through the activation of reactive oxygen species (ROS)-p38 MAPK pathway. Microarray experiments also revealed the enrichment of the gene set involved in p38 MAPK signaling in EpCAM(+) cells treated with DSF but not 5-FU. In addition, DSF appeared to downregulate Glypican 3 (GPC3) in a manner independent of ROS-p38 MAPK pathway. GPC3 was co-expressed with EpCAM in HCC cell lines and primary HCC cells and GPC3-knockdown reduced the number of EpCAM(+) cells by compromising their self-renewal capability and inducing the apoptosis. These results indicate that DSF impaired the tumorigenicity of tumor-initiating HCC cells through activation of ROS-p38 pathway and in part through the downregulation of GPC3. DSF might be a promising therapeutic agent for the eradication of tumor-initiating HCC cells. Public Library of Science 2014-01-13 /pmc/articles/PMC3890271/ /pubmed/24454751 http://dx.doi.org/10.1371/journal.pone.0084807 Text en © 2014 Chiba et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Chiba, Tetsuhiro Suzuki, Eiichiro Yuki, Kaori Zen, Yoh Oshima, Motohiko Miyagi, Satoru Saraya, Atsunori Koide, Shuhei Motoyama, Tenyu Ogasawara, Sadahisa Ooka, Yoshihiko Tawada, Akinobu Nakatsura, Tetsuya Hayashi, Takehiro Yamashita, Taro Kaneko, Syuichi Miyazaki, Masaru Iwama, Atsushi Yokosuka, Osamu Disulfiram Eradicates Tumor-Initiating Hepatocellular Carcinoma Cells in ROS-p38 MAPK Pathway-Dependent and -Independent Manners |
title | Disulfiram Eradicates Tumor-Initiating Hepatocellular Carcinoma Cells in ROS-p38 MAPK Pathway-Dependent and -Independent Manners |
title_full | Disulfiram Eradicates Tumor-Initiating Hepatocellular Carcinoma Cells in ROS-p38 MAPK Pathway-Dependent and -Independent Manners |
title_fullStr | Disulfiram Eradicates Tumor-Initiating Hepatocellular Carcinoma Cells in ROS-p38 MAPK Pathway-Dependent and -Independent Manners |
title_full_unstemmed | Disulfiram Eradicates Tumor-Initiating Hepatocellular Carcinoma Cells in ROS-p38 MAPK Pathway-Dependent and -Independent Manners |
title_short | Disulfiram Eradicates Tumor-Initiating Hepatocellular Carcinoma Cells in ROS-p38 MAPK Pathway-Dependent and -Independent Manners |
title_sort | disulfiram eradicates tumor-initiating hepatocellular carcinoma cells in ros-p38 mapk pathway-dependent and -independent manners |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3890271/ https://www.ncbi.nlm.nih.gov/pubmed/24454751 http://dx.doi.org/10.1371/journal.pone.0084807 |
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