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Elevated level of mitochondrial reactive oxygen species via fatty acid ?-oxidation in cancer stem cells promotes cancer metastasis by inducing epithelial-mesenchymal transition.

ABSTRACT:

Background

Cancer stem cells (CSCs) play a critical role in tumor development and progression and are involved in cancer metastasis. The role of reactive oxygen species (ROS) in CSCs and cancer metastasis remains controversial. The aim of the present study was to investigate the correlation between ROS level of CSCs and cancer metastasis and to explore the possible underlying molecular mechanisms.

Methods

Four different cell lines were used to isolate tumor spheres and to analyze intrinsic properties of tumor sphere cells including proliferation, self-renewal potential, differentiation, drug-resistance and cancer metastasis in vitro and in vivo. ROS assays were used to detect the intracellular ROS level of tumor spheres cells. Gene expression analysis and western blot were used to investigate the underlying mechanisms of ROS in regulating cancer metastasis.

Results

Tumor spheres possessed the characteristic features of CSCs, and ROS-high tumor spheres (RH-TS) displayed elevated mitochondrial ROS level exclusively drove metastasis formation. The gene expression analysis showed elevated fatty acid ?-oxidation, downregulation of epithelial marker upregulation of mesenchymal markers, and the activation of MAP kinase cascades. Furthermore, 14 up-regulated genes in RH-TS cells were associated with reduced overall survival of different cancer patients.

Conclusions

Our findings demonstrate that CSCs characterized by elevated mitochondrial ROS level potentiate cancer metastasis. Mechanistically, elevated mitochondrial ROS via fatty acid ?-oxidation, activates the MAPK cascades, resulting in the epithelial-mesenchymal transition (EMT) process of RH-TS cells, thereby potentiating caner invasion and metastasis. Therefore, targeting mitochondrial ROS might provide a promising approach to prevent and alleviate cancer metastasis induced by RH-TS cells.

SUBMITTER: Wang C

PROVIDER: S-EPMC6567550 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Publications

Elevated level of mitochondrial reactive oxygen species via fatty acid β-oxidation in cancer stem cells promotes cancer metastasis by inducing epithelial-mesenchymal transition.

Wang Caihua C Shao Liming L Pan Chi C Ye Jun J Ding Zonghui Z Wu Jia J Du Qin Q Ren Yuezhong Y Zhu Chunpeng C

Stem cell research & therapy 20190613 1

<h4>Background</h4>Cancer stem cells (CSCs) play a critical role in tumor development and progression and are involved in cancer metastasis. The role of reactive oxygen species (ROS) in CSCs and cancer metastasis remains controversial. The aim of the present study was to investigate the correlation between ROS level of CSCs and cancer metastasis and to explore the possible underlying molecular mechanisms.<h4>Methods</h4>Four different cell lines were used to isolate tumor spheres and to analyze ...[more]

PMID: 31196164

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