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

研究成果: ジャーナルへの寄稿記事

10 引用 (Scopus)

抄録

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.

元の言語英語
記事番号3
ジャーナルOncogenesis
6
発行部数11
DOI
出版物ステータス出版済み - 11 1 2017

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Endoplasmic Reticulum Stress
Neoplastic Stem Cells
Doxycycline
Stem Cells
Apoptosis
Neoplasms
Mitochondria
Activating Transcription Factor 4
Cell Plasticity
Anti-Bacterial Agents
Tumor Microenvironment
Electron Transport
Endoplasmic Reticulum
Antineoplastic Agents
Cell Biology
Prostatic Neoplasms
Cell Proliferation

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cancer Research

これを引用

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title = "Doxycycline induces apoptosis via ER stress selectively to cells with a cancer stem cell-like properties: Importance of stem cell plasticity",
abstract = "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.",
author = "Takashi Matsumoto and Takeshi Uchiumi and Keisuke Monji and Mikako Yagi and Daiki Setoyama and Rie Amamoto and Yuichi Matsushima and Masaki Shiota and Masatoshi Eto and Dongchon Kang",
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AU - Monji, Keisuke

AU - Yagi, Mikako

AU - Setoyama, Daiki

AU - Amamoto, Rie

AU - Matsushima, Yuichi

AU - Shiota, Masaki

AU - Eto, Masatoshi

AU - Kang, Dongchon

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