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Mitochondrial dysfunction promotes breast cancer cell migration and invasion through HIF1? accumulation via increased production of reactive oxygen species.

ABSTRACT: Although mitochondrial dysfunction has been observed in various types of human cancer cells, the molecular mechanism underlying mitochondrial dysfunction mediated tumorigenesis remains largely elusive. To further explore the function of mitochondria and their involvement in the pathogenic mechanisms of cancer development, mitochondrial dysfunction clones of breast cancer cells were generated by rotenone treatment, a specific inhibitor of mitochondrial electron transport complex I. These clones were verified by mitochondrial respiratory defect measurement. Moreover, those clones exhibited increased reactive oxygen species (ROS), and showed higher migration and invasive behaviors compared with their parental cells. Furthermore, antioxidant N-acetyl cysteine, PEG-catalase, and mito-TEMPO effectively inhibited cell migration and invasion in these clones. Notably, ROS regulated malignant cellular behavior was in part mediated through upregulation of hypoxia-inducible factor-1 ? and vascular endothelial growth factor. Our results suggest that mitochondrial dysfunction promotes cancer cell motility partly through HIF1? accumulation mediated via increased production of reactive oxygen species.

SUBMITTER: Ma J

PROVIDER: S-EPMC3726697 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Mitochondrial dysfunction promotes breast cancer cell migration and invasion through HIF1α accumulation via increased production of reactive oxygen species.

Ma Jia J Zhang Qing Q Chen Sulian S Fang Binbin B Yang Qingling Q Chen Changjie C Miele Lucio L Sarkar Fazlul H FH Xia Jun J Wang Zhiwei Z

PloS one 20130729 7

Although mitochondrial dysfunction has been observed in various types of human cancer cells, the molecular mechanism underlying mitochondrial dysfunction mediated tumorigenesis remains largely elusive. To further explore the function of mitochondria and their involvement in the pathogenic mechanisms of cancer development, mitochondrial dysfunction clones of breast cancer cells were generated by rotenone treatment, a specific inhibitor of mitochondrial electron transport complex I. These clones w ...[more]

PMID: 23922721

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Project description:BackgroundEsophageal squamous cell carcinoma (ESCC) is one of the most lethal forms of adult cancer with poor prognosis. Substantial evidence indicates that reactive oxygen species (ROS) are important modulators of aggressive cancer behavior. However, the mechanism by which ESCC cells integrate redox signals to modulate carcinoma progression remains elusive.MethodsThe expression of interferon alpha inducible protein 6 (IFI6) in clinical ESCC tissues and cell lines was detected by RT-PCR and Western blotting. The correlation between IFI6 expression levels and aggressive ESCC disease stage was examined by immunohistochemistry. Bioinformatic analysis was conducted to explore the potential function of IFI6 in ESCC. ESCC cell lines stably depleted of IFI6 and ectopically expressing IFI6 were established using lentiviruses expressing shRNAs and an IFI6 expression plasmid, respectively. The effects of IFI6 on ESCC cells were determined by cell-based analyses, including EdU assay, apoptotic assay, cellular and mitochondria-specific ROS detection, seahorse extracellular flux, and mitochondrial calcium flux assays. Blue native-polyacrylamide gel electrophoresis was used to determine mitochondrial supercomplex assembly. Transcriptional activation of NADPH oxidase 4 (NOX4) via ATF3 was confirmed by dual luciferase assay. In vivo tumor growth was determined in mouse xenograft models.ResultsWe find that the expression of IFI6, an IFN-stimulated gene localized in the inner mitochondrial membrane, is markedly elevated in ESCC patients and a panel of ESCC cell lines. High IFI6 expression correlates with aggressive disease phenotype and poor prognosis in ESCC patients. IFI6 depletion suppresses proliferation and induces apoptosis by increasing ROS accumulation. Mechanistically, IFI6 ablation induces mitochondrial calcium overload by activating mitochondrial Ca2+ uniporter and subsequently ROS production. Following IFI6 ablation, mitochondrial ROS accumulation is also induced by mitochondrial supercomplex assembly suppression and oxidative phosphorylation dysfunction, while IFI6 overexpression produces the opposite effects. Furthermore, energy starvation induced by IFI6 inhibition drives endoplasmic reticulum stress through disrupting endoplasmic reticulum calcium uptake, which upregulates NOX4-derived ROS production in an ATF3-dependent manner. Finally, the results in xenograft models of ESCC further corroborate the in vitro findings.ConclusionOur study unveils a novel redox homeostasis signaling pathway that regulates ESCC pathobiology and identifies IFI6 as a potential druggable target in ESCC.

Dataset Information

Mitochondrial dysfunction promotes breast cancer cell migration and invasion through HIF1? accumulation via increased production of reactive oxygen species.

Publications

Mitochondrial dysfunction promotes breast cancer cell migration and invasion through HIF1α accumulation via increased production of reactive oxygen species.

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