Cargando…

Doxycycline induces apoptosis via ER stress selectively to cells with a cancer stem cell-like properties: importance of stem cell plasticity

Tumor heterogeneity can be traced back to a small subset of cancer stem cells (CSCs), which can be derived from a single stem cell and show chemoresistance. Recent studies showed that CSCs are sensitive to mitochondrial targeting antibiotics such as doxycycline. However, little is known about how ca...

Descripción completa

Detalles Bibliográficos
Autores principales: Matsumoto, Takashi, Uchiumi, Takeshi, Monji, Keisuke, Yagi, Mikako, Setoyama, Daiki, Amamoto, Rie, Matsushima, Yuichi, Shiota, Masaki, Eto, Masatoshi, Kang, Dongchon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868058/
https://www.ncbi.nlm.nih.gov/pubmed/29184058
http://dx.doi.org/10.1038/s41389-017-0009-3
_version_ 1783309079119134720
author Matsumoto, Takashi
Uchiumi, Takeshi
Monji, Keisuke
Yagi, Mikako
Setoyama, Daiki
Amamoto, Rie
Matsushima, Yuichi
Shiota, Masaki
Eto, Masatoshi
Kang, Dongchon
author_facet Matsumoto, Takashi
Uchiumi, Takeshi
Monji, Keisuke
Yagi, Mikako
Setoyama, Daiki
Amamoto, Rie
Matsushima, Yuichi
Shiota, Masaki
Eto, Masatoshi
Kang, Dongchon
author_sort Matsumoto, Takashi
collection PubMed
description Tumor heterogeneity can be traced back to a small subset of cancer stem cells (CSCs), which can be derived from a single stem cell and show chemoresistance. Recent studies showed that CSCs are sensitive to mitochondrial targeting antibiotics such as doxycycline. However, little is known about how cancer cells undergo sphere formation and how antibiotics inhibit CSC proliferation. Here we show that under sphere-forming assay conditions, prostate cancer cells acquired CSC-like properties: promoted mitochondrial respiratory chain activity, expression of characteristic CSC markers and resistance to anticancer agents. Furthermore, those CSC-like properties could reversibly change depending on the culture conditions, suggesting some kinds of CSCs have plasticity in tumor microenvironments. The sphere-forming cells (i.e. cancer stem-like cells) showed increased contact between mitochondria and mitochondrial associated-endoplasmic reticulum (ER) membranes (MAM). Mitochondrial targeting doxycycline induced activating transcription factor 4 (ATF4) mediated expression of ER stress response and led to p53-upregulated modulator of apoptosis (PUMA)-dependent apoptosis only in the cancer stem-like cells. We also found that doxycycline effectively suppressed the sphere formation in vitro and blocked CD44v9-expressing tumor growth in vivo. In summary, these data provide new molecular findings that monolayer cancer cells acquire CSC-like properties in a reversible manner. These findings provide important insights into CSC biology and a potential new treatment of targeting mitochondria dependency.
format Online
Article
Text
id pubmed-5868058
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-58680582018-03-28 Doxycycline induces apoptosis via ER stress selectively to cells with a cancer stem cell-like properties: importance of stem cell plasticity Matsumoto, Takashi Uchiumi, Takeshi Monji, Keisuke Yagi, Mikako Setoyama, Daiki Amamoto, Rie Matsushima, Yuichi Shiota, Masaki Eto, Masatoshi Kang, Dongchon Oncogenesis Article Tumor heterogeneity can be traced back to a small subset of cancer stem cells (CSCs), which can be derived from a single stem cell and show chemoresistance. Recent studies showed that CSCs are sensitive to mitochondrial targeting antibiotics such as doxycycline. However, little is known about how cancer cells undergo sphere formation and how antibiotics inhibit CSC proliferation. Here we show that under sphere-forming assay conditions, prostate cancer cells acquired CSC-like properties: promoted mitochondrial respiratory chain activity, expression of characteristic CSC markers and resistance to anticancer agents. Furthermore, those CSC-like properties could reversibly change depending on the culture conditions, suggesting some kinds of CSCs have plasticity in tumor microenvironments. The sphere-forming cells (i.e. cancer stem-like cells) showed increased contact between mitochondria and mitochondrial associated-endoplasmic reticulum (ER) membranes (MAM). Mitochondrial targeting doxycycline induced activating transcription factor 4 (ATF4) mediated expression of ER stress response and led to p53-upregulated modulator of apoptosis (PUMA)-dependent apoptosis only in the cancer stem-like cells. We also found that doxycycline effectively suppressed the sphere formation in vitro and blocked CD44v9-expressing tumor growth in vivo. In summary, these data provide new molecular findings that monolayer cancer cells acquire CSC-like properties in a reversible manner. These findings provide important insights into CSC biology and a potential new treatment of targeting mitochondria dependency. Nature Publishing Group UK 2017-11-29 /pmc/articles/PMC5868058/ /pubmed/29184058 http://dx.doi.org/10.1038/s41389-017-0009-3 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Matsumoto, Takashi
Uchiumi, Takeshi
Monji, Keisuke
Yagi, Mikako
Setoyama, Daiki
Amamoto, Rie
Matsushima, Yuichi
Shiota, Masaki
Eto, Masatoshi
Kang, Dongchon
Doxycycline induces apoptosis via ER stress selectively to cells with a cancer stem cell-like properties: importance of stem cell plasticity
title Doxycycline induces apoptosis via ER stress selectively to cells with a cancer stem cell-like properties: importance of stem cell plasticity
title_full Doxycycline induces apoptosis via ER stress selectively to cells with a cancer stem cell-like properties: importance of stem cell plasticity
title_fullStr Doxycycline induces apoptosis via ER stress selectively to cells with a cancer stem cell-like properties: importance of stem cell plasticity
title_full_unstemmed Doxycycline induces apoptosis via ER stress selectively to cells with a cancer stem cell-like properties: importance of stem cell plasticity
title_short Doxycycline induces apoptosis via ER stress selectively to cells with a cancer stem cell-like properties: importance of stem cell plasticity
title_sort doxycycline induces apoptosis via er stress selectively to cells with a cancer stem cell-like properties: importance of stem cell plasticity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868058/
https://www.ncbi.nlm.nih.gov/pubmed/29184058
http://dx.doi.org/10.1038/s41389-017-0009-3
work_keys_str_mv AT matsumototakashi doxycyclineinducesapoptosisviaerstressselectivelytocellswithacancerstemcelllikepropertiesimportanceofstemcellplasticity
AT uchiumitakeshi doxycyclineinducesapoptosisviaerstressselectivelytocellswithacancerstemcelllikepropertiesimportanceofstemcellplasticity
AT monjikeisuke doxycyclineinducesapoptosisviaerstressselectivelytocellswithacancerstemcelllikepropertiesimportanceofstemcellplasticity
AT yagimikako doxycyclineinducesapoptosisviaerstressselectivelytocellswithacancerstemcelllikepropertiesimportanceofstemcellplasticity
AT setoyamadaiki doxycyclineinducesapoptosisviaerstressselectivelytocellswithacancerstemcelllikepropertiesimportanceofstemcellplasticity
AT amamotorie doxycyclineinducesapoptosisviaerstressselectivelytocellswithacancerstemcelllikepropertiesimportanceofstemcellplasticity
AT matsushimayuichi doxycyclineinducesapoptosisviaerstressselectivelytocellswithacancerstemcelllikepropertiesimportanceofstemcellplasticity
AT shiotamasaki doxycyclineinducesapoptosisviaerstressselectivelytocellswithacancerstemcelllikepropertiesimportanceofstemcellplasticity
AT etomasatoshi doxycyclineinducesapoptosisviaerstressselectivelytocellswithacancerstemcelllikepropertiesimportanceofstemcellplasticity
AT kangdongchon doxycyclineinducesapoptosisviaerstressselectivelytocellswithacancerstemcelllikepropertiesimportanceofstemcellplasticity