Tip-cell behavior is regulated by transcription factor FoxO1 under hypoxic conditions in developing mouse retinas

Fukumoto, Moe; Kanako, Kondo; Uni, Kazumasa; Ishiguro, Tomoko; Hayashi, Mikiko; Ueda, Satoshi; Itsuki, Mori; Niimi, Kenta; Tashiro, Fumi; Miyazaki, Satsuki; Miyazaki, Junichi; Inagaki, Shinobu; Furuyama, Tatsuo

doi:10.1007/s10456-017-9588-z

Cited by 43 publications

(37 citation statements)

References 30 publications

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“…Human umbilical vein endothelial cell line (HUVEC) were obtained from the American Type Culture Collection (Manassas, VA). Hyperglycemia stress was induced via incubating HUVEC with 25 mmol/L high‐glucose‐medium, in accordance with a recent study (Fukumoto et al, ; Gianni‐Barrera et al, ). The Mst1 siRNA and the control siRNA were constructed Shanghai GenePharma Co., Ltd., (Shanghai, China; Iban‐Arias et al, ; Jo et al, ).…”

Section: Methodssupporting

confidence: 86%

Mst1 deletion reduces hyperglycemia‐mediated vascular dysfunction via attenuating mitochondrial fission and modulating the JNK signaling pathway

Qin

Lin

Zhang

et al. 2019

Journal Cellular Physiology

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Diabetes is a leading cause of microvascular complications, such as nephropathy and retinopathy. Recent studies have proposed that hyperglycemia-induced endothelial cell dysfunction is modulated by mitochondrial stress. Therefore, our experiment was to detect the upstream mediator of mitochondrial stress in hyperglycemia-treated endothelial cells with a focus on macrophage-stimulating 1 (Mst1) and mitochondrial fission. Our data illuminated that hyperglycemia incubation reduced cell viability, as well as increased apoptosis ratio in endothelial cell, and this alteration seemed to be associated with Mst1 upregulation. Inhibition of Mst1 via transfection of Mst1 siRNA into an endothelial cell could sustain cell viability and maintain mitochondrial function. At the molecular levels, endothelial cell death was accompanied with the activation of mitochondrial oxidative stress, mitochondrial apoptosis, and mitochondrial fission. Genetic ablation of Mst1 could reduce mitochondrial oxidative injury, block mitochondrial apoptosis, and repress mitochondrial fission. Besides, we also found Mst1 triggered mitochondrial dysfunction as well as endothelial cell damage through augmenting JNK pathway. Suppression of JNK largely ameliorated the protective actions of Mst1 silencing on hyperglycemia-treated endothelial cells and sustain mitochondrial function. The present study identifies Mst1 as a primary key mediator for hyperglycemia-induced mitochondrial damage and endothelial cell dysfunction. Increased Mst1 impairs mitochondrial function and activates endothelial cell death via opening mitochondrial death pathway through JNK. K E Y W O R D S endothelial cells, hyperglycemia, JNK pathway, mitochondria, Mst1

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Section: Methodssupporting

confidence: 86%

Mst1 deletion reduces hyperglycemia‐mediated vascular dysfunction via attenuating mitochondrial fission and modulating the JNK signaling pathway

Qin

Lin

Zhang

et al. 2019

Journal Cellular Physiology

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“…7). Based on our results, the Sirt3-JNK-Fis1 signaling pathway should be considered as a potential target to treat tongue cancer via inducing cell apoptosis and mitochondrial stress (Fukumoto et al 2018). Notably, more investigations in animal research and clinical practice are required to obtain more complete elucidation of the properties of Sirt3modified Fis1 mitochondrial fission in tongue cancer death.…”

Section: Discussionmentioning

confidence: 77%

RETRACTED ARTICLE: Sirtuin 3 inhibition induces mitochondrial stress in tongue cancer by targeting mitochondrial fission and the JNK-Fis1 biological axis

Zhou

Shi

et al. 2019

Cell Stress and Chaperones

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Sirtuin 3 (Sirt3)-modified mitochondrial fission participates in the progression of several types of cancers. However, its role in tongue cancer requires investigation. The aim of our study is to determine whether Sirt3 knockdown regulates the viability of tongue cancer cells via modulating mitochondrial fission. Two types of tongue cancer cells were used in the present study, and siRNA was transfected into the cells to suppress Sirt3 expression. Mitochondrial function and cell apoptosis were determined via immunofluorescence, Western blotting, ELISA, and qPCR assays. A pathway blocker was applied to verify the role of the JNK-Fis1 signaling pathway in regulation of mitochondrial fission. The present study showed that loss of Sirt3 promoted tongue cancer cell death in a manner dependent on mitochondrial apoptosis. Mitochondrial oxidative stress, energy metabolism disorder, mitochondrial cyt-c liberation, and mitochondrial apoptosis activation were observed after Sirt3 silencing. Furthermore, we demonstrated that Sirt3 knockdown activated mitochondrial stress via triggering Fis1-related mitochondrial fission and that inhibition of Fis1-related mitochondrial fission abrogated the pro-apoptotic effect of Sirt3 knockdown on tongue cancer cells. To this end, we found that Sirt3 modulated Fis1 expression via the c-Jun N-terminal kinases (JNK) signaling pathway and that blockade of the JNK pathway attenuated mitochondrial stress and repressed apoptosis in Sirt3 knockdown cells. Altogether, our results identified a tumor-suppressive role for Sirt3 deficiency in tongue cancer via activation of the JNK-Fis1 axis and subsequent initiation of fatal mitochondrial fission. Given these findings, strategies to repress Sirt3 activity and enhance the JNK-Fis1mitochondrial fission cascade have clinical benefits for patients with tongue cancer.

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“…For Transwell migration assays, the upper chambers of 24-well Transwell assay plates were seeded with 2 × 10 3 HepG2 cells in 200 μL serum-free medium per well. The lower chambers were filled with 600 μL medium containing 0.5% FBS [ 45 ]. After a 24-h incubation in a humidified incubator at 37 °C, 5% CO 2 , cells that had migrated to the underside of the membranes were fixed and stained with 0.1% crystal violet.…”

Section: Methodsmentioning

confidence: 99%

TAZ inhibition promotes IL-2-induced apoptosis of hepatocellular carcinoma cells by activating the JNK/F-actin/mitochondrial fission pathway

Lin

Wang

et al. 2018

Cancer Cell Int

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BackgroundCytokine-based cancer therapies have attracted a great deal of attention in recent years. Unfortunately, resistance to treatment limits the efficacy of these therapeutics. Therefore, the aim of our study was to explore the mechanism of IL-2-based therapy for hepatocellular carcinoma in an attempt to increase the efficiency of this treatment option.MethodsHepG2 cells were treated with IL-2. Then, siRNA against TZA was used to transfected into HepG2 cells. Cellular apoptosis was measured via MTT assay, TUNEL assay and caspase-3 activity. Cellular proliferation was evaluated via EdU assay and western blotting. Cellular migration was detected via Transwell assay. Mitochondrial function was monitored by mitochondrial potential analysis, ROS staining, immunofluorescence and western blotting. Pathway blocker and activator were used to establish the role of JNK/F-actin/mitochondrial fission signaling pathway in HepG2 cells stress response.ResultsOur study found that IL-2 treatment significantly reduced the viability, mobility and proliferation of HepG2 cells in vitro. We also demonstrated that IL-2 treatment was accompanied by an increase in the expression of transcriptional co-activator with PDZ-binding motif (TAZ). Interestingly, genetic ablation of TAZ in the presence of IL-2 further promoted apoptosis, inhibited mobility, and arrested proliferation in HepG2 cells. At the molecular level, IL-2 administration activated excessive mitochondrial fission via the JNK/F-actin pathway; these effects were further enhanced by TAZ deletion. Mechanistically, TAZ knockdown further increased the expression of mitochondrial fission-related proteins such as Drp1, Mff and Fis. The augmented mitochondrial fission stimulated ROS overproduction, mediated redox imbalance, interrupted mitochondrial energy generation, reduced mitochondrial membrane potential, promoted leakage of the pro-apoptotic molecule cyt-c into the nucleus, and initiated caspase-9-related mitochondrial death. Further, we demonstrated that the anti-proliferative and anti-metastatic effects of IL-2 in HepG2 cells were enhanced by TAZ deletion, suggesting that IL-2 sensitizes HepG2 cells to IL-2-based cytokine therapy. However, JNK/F-actin pathway blockade could abrogate the inhibitory effects of TAZ deletion on HepG2 migration, proliferation and survival.ConclusionsTaken together, our data indicate that the anti-tumor effects of IL-2-based therapies may be enhanced by TAZ deletion in a JNK/F-actin pathway-dependent manner. This finding provides a novel combinatorial therapeutic approach for treating hepatocellular carcinoma that might significantly increase the efficacy of cytokine-based therapies in a clinical setting.Electronic supplementary materialThe online version of this article (10.1186/s12935-018-0615-y) contains supplementary material, which is available to authorized users.

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Tip-cell behavior is regulated by transcription factor FoxO1 under hypoxic conditions in developing mouse retinas

Cited by 43 publications

References 30 publications

Mst1 deletion reduces hyperglycemia‐mediated vascular dysfunction via attenuating mitochondrial fission and modulating the JNK signaling pathway

Mst1 deletion reduces hyperglycemia‐mediated vascular dysfunction via attenuating mitochondrial fission and modulating the JNK signaling pathway

RETRACTED ARTICLE: Sirtuin 3 inhibition induces mitochondrial stress in tongue cancer by targeting mitochondrial fission and the JNK-Fis1 biological axis

TAZ inhibition promotes IL-2-induced apoptosis of hepatocellular carcinoma cells by activating the JNK/F-actin/mitochondrial fission pathway

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