Mitochondrial dysfunction induces EMT through the TGF-β/Smad/Snail signaling pathway in Hep3B hepatocellular carcinoma cells

Yi, Eui-Yeun; Park, Shi-Young; Jung, Seung‐Hyun; Jang, Won‐Jun; Kim, Yung-Jin

doi:10.3892/ijo.2015.3154

Cited by 44 publications

(29 citation statements)

References 37 publications

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“…For example, OXPHOS dysfunction has been reported to be involved in cell migration, invasion and metastasis (32). In addition, it was recently demonstrated that mitochondrial dysfunction promotes EMT through the transforming growth factor (TGF)-β/Smad/Snail signaling pathway by activating c-Jun/activator protein-1 in hepatocellular carcinoma cells (33). Another study also demonstrated that mitochondrial dysfunction following TGFβ-1 exposure induces acquisition of a mesenchymal morphology and the transfer from an epithelial to a mesenchymal phenotype in pancreatic cancer (28).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction induces the invasive phenotype, and cell migration and invasion, through the induction of AKT and AMPK pathways in lung cancer cells

et al. 2018

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Mitochondria are well known for their important roles in oxidative phosphorylation, amino acid metabolism, fatty acid oxidation and ion homeostasis. Although the effects of mitochondrial dysfunction on tumorigenesis in various cancer cells have been reported, the correlation between mitochondrial dysfunction and epithelial‑to‑mesenchymal transition (EMT) in lung cancer development and metastasis has not been well elucidated. In the present study, the effects of mitochondrial dysfunction on EMT and migration in lung cancer cells were investigated using inhibitors of mitochondrial respiration, oligomycin A and antimycin A. Oligomycin A and antimycin A induced distinct mesenchymal‑like morphological features in H23, H1793 and A549 lung cancer cells. In addition, they decreased the expression levels of the epithelial marker protein E‑cadherin, but increased the expression levels of the mesenchymal marker proteins Vimentin, Snail and Slug. The results of immunofluorescence staining indicated that oligomycin A and antimycin A downregulated cortical E‑cadherin expression and upregulated the expression of Vimentin. In addition, oligomycin A and antimycin A increased the migration and invasion of A549 lung cancer cells, and promoted the expression levels of phosphorylated (p)‑protein kinase B (AKT) and p‑AMP‑activated protein kinase (AMPK). Notably, the production of reactive oxygen species by oligomycin A and antimycin A did not affect the expression of EMT protein markers. Conversely, treatment with the AKT inhibitor wortmannin and the AMPK inhibitor Compound C upregulated E‑cadherin and downregulated Vimentin expression. These results suggested that oligomycin A and antimycin A may induce migration and invasion of lung cancer cells by inducing EMT via the upregulation of p‑AKT and p‑AMPK expression.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction induces the invasive phenotype, and cell migration and invasion, through the induction of AKT and AMPK pathways in lung cancer cells

et al. 2018

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“…The EMT process can be induced in several cancer cell lines ( 69 – 71 ), usually by TGF-β1 addition or hypoxia, the most common inducers ( 72 ).…”

Section: Epithelial-to-mesenchymal Transition: Differences Between Nomentioning

confidence: 99%

Glycosylation in Cancer: Interplay between Multidrug Resistance and Epithelial-to-Mesenchymal Transition?

et al. 2016

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The expression of unusual glycan structures is a hallmark of cancer progression, and their functional roles in cancer biology have been extensively investigated in epithelial-to-mesenchymal transition (EMT) models. EMT is a physiological process involved in embryonic development and wound healing. It is characterized by loss of epithelial cell polarity and cell adhesion, permitting cell migration, and thus formation of new epithelia. However, this process is unwanted when occurring outside their physiological limit, resulting in fibrosis of organs and progression of cancer and metastasis. Several studies observed that EMT is related to the acquisition of multidrug resistance (MDR) phenotype, a condition in which cancer cells acquire resistance to multiple different drugs, which has virtually nothing in common. However, although some studies suggested interplay between these two apparently distinct phenomena, almost nothing is known about this possible relationship. A common pathway to them is the need for glycosylation, a post-translational modification that can alter biological function. Thus, this review intends to compile the main facts obtained until now in these two areas, as an effort to unravel the relationship between EMT and MDR.

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“…Previous work from our laboratory has highlighted the role of both the hypothalamic NF-B (67,89,94,96) and TGF␤ (89) pathways in metabolic syndrome. Considering that mitochondrial dysfunction (90) and mtDNA (31) are known to trigger activation of the TGFß pathway, we studied levels of downstream signaling molecules including Smad and ERK1/2 via Western blot of hypothalamic tissues. Analysis of hypothalamic proteins revealed that a single hypothalamic infusion of mtDNA increased levels of phosphorylated Smad2 and ERK1/2 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Obesity-associated extracellular mtDNA activates central TGFβ pathway to cause blood pressure increase

Ale

Zhang

Han

et al. 2017

American Journal of Physiology-Endocrinology and Metabolism

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Hypothalamic inflammation was recently found to mediate obesity-related hypertension, but the responsible upstream mediators remain unexplored. In this study, we show that dietary obesity is associated with extracellular release of mitochondrial DNA (mtDNA) into the cerebrospinal fluid and that central delivery of mtDNA mimics transforming growth factor-β (TGFβ) excess to activate downstream signaling pathways. Physiological study reveals that central administration of mtDNA or TGFβ is sufficient to cause hypertension in mice. Knockout of the TGFβ receptor in proopiomelanocortin neurons counteracts the hypertensive effect of not only TGFβ but also mtDNA excess, while the hypertensive action of central mtDNA can be blocked pharmacologically by a TGFβ receptor antagonist or genetically by TGFβ receptor knockout. Finally, we confirm that obesity-induced hypertension can be reversed through central treatment with TGFβ receptor antagonist. In conclusion, circulating mtDNA in the brain employs neural TGFβ pathway to mediate a central inflammatory mechanism of obesity-related hypertension.

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Mitochondrial dysfunction induces EMT through the TGF-β/Smad/Snail signaling pathway in Hep3B hepatocellular carcinoma cells

Cited by 44 publications

References 37 publications

Mitochondrial dysfunction induces the invasive phenotype, and cell migration and invasion, through the induction of AKT and AMPK pathways in lung cancer cells

Mitochondrial dysfunction induces the invasive phenotype, and cell migration and invasion, through the induction of AKT and AMPK pathways in lung cancer cells

Glycosylation in Cancer: Interplay between Multidrug Resistance and Epithelial-to-Mesenchymal Transition?

Obesity-associated extracellular mtDNA activates central TGFβ pathway to cause blood pressure increase

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