scholarly journals Hypoxia-Induced ROS Promotes Mitochondrial Fission and Cisplatin Chemosensitivity via HIF-1α/Mff Regulation

2020 ◽  
Author(s):  
Kun Wu ◽  
Yuan-yuan Mao ◽  
Qi Chen ◽  
Bolin Zhang ◽  
Sheng Zhang ◽  
...  
Keyword(s):  
Malignant Tumors ◽  
Mitochondrial Dynamics ◽  
Dynamic Balance ◽  
Mitochondrial Fission ◽  
Hypoxia Inducible Factor ◽  
Hypoxic Condition ◽  
Clinical Samples ◽  
Α Subunit ◽  
Hypoxic Conditions ◽  
Underlying Mechanisms

Abstract BackgroundChemotherapy treatment based on Cisplatin (CDDP) is established as the drug of choice for head and neck squamous cell carcinoma (HNSCC). Malignant tumors respond to microenvironment alteration through a dynamic balance of mitochondrial fission and fusion. HNSCC is known to have hypoxic conditions, yet the effects and underlying mechanisms of hypoxia on chemosensitivity and mitochondrial dynamics remain unclear. ResultsWe found that hypoxia promoted mitochondrial fission and CDDP sensitivity in HNSCC cells. Importantly, Mff was shown to be correlated with chemosensitivity in clinical samples of HNSCC that underwent a hypoxic condition. Hypoxia-inducible factor 1 α-subunit (HIF-1α) dramatically increased Mff transcriptional expression and directly bound to Mff. Hypoxia enhanced the release of reactive oxygen species (ROS) and upregulated the expression of Mff via HIF-1α in HNSCC cells. ROS depletion in HNSCC cells attenuated HIF-1α, Mff expression, and mitochondrial fission. Moreover, a knockdown of Mff suppressed hypoxia-induced mitochondrial fission and decreased CDDP chemosensitivity in vivo and in vitro. ConclusionsOur findings revealed that the hypoxia-induced release of ROS promoted mitochondrial fission and CDDP chemosensitivity via the regulation of HIF-1α/Mff in HNSCC cells, indicating that Mff may serve as a new biomarker to predict neoadjuvant chemosensitivity in HNSCC patients.

scholarly journals Hypoxia-Induced ROS Promotes Mitochondrial Fission and Cisplatin Chemosensitivity via HIF-1α/Mff Regulation

2020 ◽  
Author(s):  
Kun Wu ◽  
Yuan-yuan Mao ◽  
Qi Chen ◽  
Bolin Zhang ◽  
Sheng Zhang ◽  
...  
Keyword(s):  
Malignant Tumors ◽  
Mitochondrial Dynamics ◽  
Dynamic Balance ◽  
Mitochondrial Fission ◽  
Hypoxia Inducible Factor ◽  
Hypoxic Condition ◽  
Clinical Samples ◽  
Hypoxic Conditions

Chemotherapy treatment based on Cisplatin (CDDP) is established as the drug of choice for head and neck squamous cell carcinoma (HNSCC). Malignant tumors respond to microenvironment alteration through a dynamic balance of mitochondrial fission and fusion. HNSCC is known to have hypoxic conditions, yet the effects and underlying mechanisms of hypoxia on chemosensitivity and mitochondrial dynamics remain unclear. We found that hypoxia promoted mitochondrial fission and CDDP sensitivity in HNSCC cells. Importantly, Mff was shown to be correlated with chemosensitivity in clinical samples of HNSCC that underwent a hypoxic condition. Hypoxia-inducible factor 1 α-subunit (HIF-1α) dramatically increased Mff transcriptional expression and directly bound to Mff. Hypoxia enhanced the release of reactive oxygen species (ROS) and upregulated the expression of Mff via HIF-1α in HNSCC cells. ROS depletion in HNSCC cells attenuated HIF-1α, Mff expression, and mitochondrial fission. Moreover, a knockdown of Mff suppressed hypoxia-induced mitochondrial fission and decreased CDDP chemosensitivity in vivo and in vitro. Our findings revealed that the hypoxia-induced release of ROS promoted mitochondrial fission and CDDP chemosensitivity via the regulation of HIF-1α/Mff in HNSCC cells, indicating that Mff may serve as a new biomarker to predict neoadjuvant chemosensitivity in HNSCC patients

scholarly journals The effect of hyaluronic acid on nucleus pulposus extracellular matrix production through hypoxia-inducible factor-1α transcriptional activation of CD44 under hypoxia

2021 ◽  
Vol 41 ◽  
pp. 142-152
Author(s):  
F Zhang ◽  
◽  
X Liu ◽  
B Li ◽  
Z Li ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Hyaluronic Acid ◽  
Nucleus Pulposus ◽  
Transcriptional Activation ◽  
Hypoxia Inducible Factor ◽  
Hypoxic Condition ◽  
Nucleus Pulposus Cells ◽  
Cd44 Expression ◽  
Hypoxia Inducible Factor 1Α ◽  
Hypoxic Conditions

Intervertebral disc degeneration (IDD) is the leading cause of low-back pain. Implantation of hyaluronic acid (HA) is potentially a therapeutic strategy for IDD, but its pharmacological effects and mechanism under hypoxic conditions remain unclear. In this study, the expression of extracellular matrix genes and proteins were enhanced in nucleus pulposus cells (NPCs) in the presence of HA under hypoxic condition, as shown by real-time reverse transcription-polymerase chain reaction, immunofluorescence staining, and dimethylmethylene blue assays. Moreover, the expression of CD44 was increased in the presence of both HA and hypoxia compared to either alone. Using a bioinformatic database, hypoxia inducible factor-1α (HIF-1α), a key transcription factor in the hypoxic condition, was found to have 4 predicted binding sites on the CD44 promoter. CD44 expression was significantly increased by treatment with cobalt chloride or dimethyloxalylglycine. Over-expression of HIF-1α in NPCs significantly up-regulated the expression of CD44. The binding site of HIF-1α in the CD44 promoter region, was identified by promoter truncation experiments and chromatin immunoprecipitation assays. Taken together, these results indicated that hypoxic conditions positively potentiated the ability of NPCs matrix synthesis in the presence of HA, which correlated with the increasing CD44 expression by HIF-1α transcriptional activation.

scholarly journals Combined Cornus Officinalis and Paeonia Lactiflora Pall Therapy Alleviates Rheumatoid Arthritis by Regulating Synovial Apoptosis via AMPK-Mediated Mitochondrial Fission

2021 ◽  
Vol 12 ◽  
Author(s):  
Lichuang Huang ◽  
Shaoqi Hu ◽  
Meiyu Shao ◽  
Xin Wu ◽  
Jida Zhang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Bone Erosion ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Cartilage Destruction ◽  
Paeonia Lactiflora ◽  
Active Components ◽  
Cornus Officinalis ◽  
Medicinal Value ◽  
Underlying Mechanisms

Rheumatoid arthritis (RA) is a chronic autoimmune disease that leads to cartilage destruction and bone erosion. In-depth exploration of the pathogenesis of RA and the development of effective therapeutic drugs are of important clinical and social value. Herein, we explored the medicinal value of Cornus officinalis Sieb. and Paeonia lactiflora Pall. in RA treatment using a rat model of collagen-induced arthritis (CIA). We compared the therapeutic effect of Cornus officinalis and Paeonia lactiflora with that of their main active compounds, ursolic acid and paeoniflorin, respectively. We demonstrated that the combination of Cornus officinalis and Paeonia lactiflora effectively inhibited the release of factors associated with oxidative stress and inflammation during RA, therein ameliorating the symptoms and suppressing the progression of RA. We further showed that the underlying mechanisms may be related to the regulation of apoptosis in synovial tissues, and we investigated the potential involvement of AMPK-mediated mitochondrial dynamics in the therapeutic action of the two drugs and their active components.

scholarly journals Regulation of mitochondrial dynamics in 2-methoxyestradiol-mediated osteosarcoma cell death

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Magdalena Gorska-Ponikowska ◽  
Paulina Bastian ◽  
Agata Zauszkiewicz-Pawlak ◽  
Agata Ploska ◽  
Adrian Zubrzycki ◽  
...  
Keyword(s):  
Malignant Tumors ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
In Vivo Studies ◽  
Childhood And Adolescence ◽  
Osteosarcoma Cell ◽  
Intrinsic Apoptosis ◽  
Apoptosis Pathway ◽  
Bax Protein ◽  
Intrinsic Apoptosis Pathway

AbstractOsteosarcoma (OS) is one of the most malignant tumors of childhood and adolescence. Research on mitochondrial dynamics (fusion/fission) and biogenesis has received much attention in last few years, as they are crucial for death of cancer cells. Specifically, it was shown that increased expression of the cytoplasmic dynamin-related protein 1 (Drp1) triggers mitochondrial fission (division), which activates BAX and downstream intrinsic apoptosis, effectively inhibiting OS growth. In the presented study, human OS cells (metastatic 143B OS cell line) were incubated with 2-methoxyestradiol (2-ME) at both physiologically and pharmacologically relevant concentrations. Cell viability was determined by the MTT assay. Confocal microscopy and western blot methods were applied to examine changes in Drp1 and BAX protein levels. Mitochondrial Division Inhibitor 1, MDIVI-1, was used in the study to further examine the role of Drp1 in 2-ME-mediated mechanism of action. To determine quantitative and qualitative changes in mitochondria, electron microscopy was used. 2-ME at all used concentrations increased mitochondrial fission and induced autophagy in OS cells. At the concentration of 1 µM 2-ME increased the area density of mitochondria in OS cells. Subsequent, upregulated expression of Drp1 and BAX proteins by 2-ME strongly suggests the activation of the intrinsic apoptosis pathway. We further observed 2-ME-mediated regulation of glycolytic state of OS cells. Therefore, we suggest that changes of mitochondrial dynamics may represent a novel mechanism of anticancer action of 2-ME. This finding may open new approaches to improve the efficacy of chemotherapy in the treatment of OS, however, it has to be confirmed by in vivo studies.

scholarly journals Hypoxia-Induced Autophagy Enhances Cisplatin Resistance in Human Bladder Cancer Cells by Targeting Hypoxia-Inducible Factor-1α

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Xiawa Mao ◽  
Nanzhang ◽  
Jiaquao Xiao ◽  
Huifeng Wu ◽  
Kefeng Ding
Keyword(s):  
Bladder Cancer ◽  
Cancer Cells ◽  
Hypoxia Inducible Factor ◽  
Cancer Cell Line ◽  
Hypoxic Condition ◽  
Underlying Mechanism ◽  
Bladder Cancer Cell Line ◽  
Hypoxic Conditions ◽  
Bladder Cancer Cells ◽  
Autophagy Pathway

Purpose. To investigate the effect of hypoxia on chemoresistance and the underlying mechanism in bladder cancer cells. Methods. BIU-87 bladder cancer cell line was treated with cisplatin under hypoxic and normoxic conditions and tested using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, and Western blotting. All the data were expressed as mean ± standard   error from three independent experiments and analyzed by multiple t -tests. Results. Apoptosis of bladder cancer cells caused by cisplatin was attenuated in hypoxic conditions. Hypoxia enhanced autophagy caused by cisplatin. The autophagy inhibitor and HIF-1α inhibitor can reverse the chemoresistance in hypoxic condition. Apoptosis and autophagy of bladder cancer cells were downregulated by HIF-1α inhibitor YC-1. Hypoxia-induced autophagy enhanced chemoresistance to cisplatin via the HIF-1 signaling pathway. Conclusion. Resistance to cisplatin in BIU-87 bladder cancer cells under hypoxic conditions can be explained by activation of autophagy, which is regulated by HIF-1α-associated signaling pathways. The hypoxia–autophagy pathway may be a target for improving the efficacy of cisplatin chemotherapy in bladder cancer.

The cross-talk between NF-κB and HIF-1: further evidence for a significant liaison

2008 ◽  
Vol 412 (3) ◽  
pp. e17-e19 ◽  
Author(s):  
Agnes Görlach ◽  
Steve Bonello
Keyword(s):  
Oxidative Stress ◽  
Cellular Response ◽  
Distinct Element ◽  
Hypoxia Inducible Factor ◽  
Nuclear Factor Κb ◽  
Proximal Promoter ◽  
Α Subunit ◽  
Hypoxic Conditions ◽  
Tnf Α ◽  
And Oxidative Stress

HIF-1 (hypoxia-inducible factor-1) has been shown to essentially control the cellular response to hypoxia. Hypoxia stabilizes the inducible α-subunit, preventing post-translational hydroxylation and subsequent degradation via the proteasome. In recent years, clear evidence has emerged that HIF-1α is also responsive to many stimuli under normoxic conditions, including thrombin, growth factors, vasoactive peptides, insulin, lipopolysaccharide and cytokines such as TNF-α (tumour necrosis factor-α), and in many cases reactive oxygen species are involved. One important mechanism underlying these responses is the transcriptional regulation of HIF-1α by the redox-sensitive transcription factor NF-κB (nuclear factor κB), which binds at a distinct element in the proximal promoter of the HIF-1α gene. More recently, NF-κB binding to this site in the HIF-1α promoter has been shown also under hypoxic conditions. Thus these two major pathways regulating the responses to inflammation and oxidative stress on the one hand, and hypoxia on the other hand, appear to be intimately linked. In this issue of the Biochemical Journal, a study by van Uden et al. has supported these findings further, in which they have confirmed the binding of several proteins of the NF-κB family at the previously identified consensus site in the HIF-1α promoter and shown that TNF-α can also transcriptionally induce HIF-1α by this previously described pathway. The identification of HIF-1α as a target gene of NF-κB will have important implications for a variety of disorders related to hypoxia–ischaemia and/or inflammation and oxidative stress.

scholarly journals IOP1, a novel hydrogenase-like protein that modulates hypoxia-inducible factor-1α activity

2006 ◽  
Vol 401 (1) ◽  
pp. 341-352 ◽  
Author(s):  
Jianhe Huang ◽  
Daisheng Song ◽  
Adrian Flores ◽  
Quan Zhao ◽  
Sharon M. Mooney ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Hypoxia Inducible Factor ◽  
Cell Types ◽  
Mrna Levels ◽  
Low Oxygen ◽  
Gene Expressions ◽  
Iron Sulfur Cluster ◽  
Α Subunit ◽  
Protein Levels ◽  
Hypoxic Conditions

A central means by which mammalian cells respond to low oxygen tension is through the activation of the transcription factor HIF-1 (hypoxia-inducible factor-1). Under normoxic conditions, HIF-1α (the α subunit of HIF-1) is targeted for rapid degradation by the ubiquitin–proteasome pathway. Under hypoxic conditions, this degradation is inhibited, thereby leading to the stabilization and activation of HIF-1α. Here, we report the identification of IOP1 (iron-only hydrogenase-like protein 1), a protein homologous with enzymes present in anaerobic organisms that contain a distinctive iron–sulfur cluster. IOP1 is present in a broad range of cell types. Knockdown of IOP1 using siRNA (small interfering RNA) in mammalian cells increases protein levels of HIF-1α under both normoxic and hypoxic conditions, and augments hypoxia-induced HRE (hypoxia response element) reporter gene and endogenous HIF-1α target gene expressions. We find that IOP1 knockdown up-regulates HIF-1α mRNA levels, thereby providing a mechanism by which knockdown induces the observed effects. The results collectively provide evidence that IOP1 is a component of the protein network that regulates HIF-1α in mammalian cells.

scholarly journals Acriflavine, a Potent Inhibitor of HIF-1α, Disturbs Glucose Metabolism and Suppresses ATF4-Protective Pathways in Melanoma under Non-Hypoxic Conditions

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 102
Author(s):  
Román Martí-Díaz ◽  
María F. Montenegro ◽  
Juan Cabezas-Herrera ◽  
Colin R. Goding ◽  
José Neptuno Rodríguez-López ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Potent Inhibitor ◽  
Hypoxia Inducible Factor ◽  
Hypoxic Condition ◽  
Melanoma Cells ◽  
Pyruvate Dehydrogenase Kinase ◽  
Hypoxic Conditions ◽  
Activating Transcription Factor 4 ◽  
Elevated Expression ◽  
Pyruvate Dehydrogenase Kinase 1

Hypoxia-inducible factor (HIF)-1α is constitutively expressed in melanoma cells under normoxic conditions and its elevated expression correlates with the aggressiveness of melanoma tumors. Here, we used acriflavine, a potent inhibitor of HIF-1α dimerization, as a tool to investigate whether HIF-1α-regulated pathways contribute to the growth of melanoma cells under normoxia. We observed that acriflavine differentially modulated HIF-1α-regulated targets in melanoma under normoxic conditions, although acriflavine treatment resulted in over-expression of vascular endothelial growth factor (VEGF), its action clearly downregulated the expression of pyruvate dehydrogenase kinase 1 (PDK1), a well-known target of HIF-1α. Consequently, downregulation of PDK1 by acrifavine resulted in reduced glucose availability and suppression of the Warburg effect in melanoma cells. In addition, by inhibiting the AKT and RSK2 phosphorylation, acriflavine also avoided protective pathways necessary for survival under conditions of oxidative stress. Interestingly, we show that acriflavine targets activating transcription factor 4 (ATF4) for proteasomal degradation while suppressing the expression of microphthalmia-associated transcription factor (MITF), a master regulator of melanocyte development and a melanoma oncogene. Since acriflavine treatment results in the consistent death of melanoma cells, our results suggest that inhibition of HIF-1α function in melanoma could open new avenues for the treatment of this deadly disease regardless of the hypoxic condition of the tumor.

How do cells adapt to oxygen availability – the role of hypoxia-inducible factor HIF-1

2020 ◽  
Vol 56 (1) ◽  
pp. 23-26
Author(s):  
Grażyna Sygitowicz ◽  
Dariusz Sitkiewicz
Keyword(s):  
Transcription Factor ◽  
Energy Metabolism ◽  
Aerobic Glycolysis ◽  
Hypoxia Inducible Factor ◽  
Oxygen Availability ◽  
Α Subunit ◽  
Hypoxic Conditions ◽  
Active Transcription ◽  
Adaptation Processes

Thanks to the works of this year`s Nobel Laureates, we know much more about how different oxygen levels regulate fundamental physiological and pathophysiological processes. Variable oxygen availability requires the activation of multiple adaptation processes from cells. Inhibition of the degradation of α subunit of the hypoxia-inducible factor (HIF-1) is a key reaction of cells to hypoxic conditions. These conditions lead to generation of the active transcription factor – dimer HIF-1α/β, which activates the expression of plenty of genes. HIF-1 is then accumulated in the nucleus and binded to DNA in hypoxia-regulated genes. The products of these genes are involved in generation of new blood vessels (VEGF), erytropoesis process (EPO) and in energy metabolism in mitochondria from oxidative phosphorylation to aerobic glycolysis (LDH, phosphoglycero kinase, aldolase and GLUT1).

scholarly journals CXCR4 promotes B cell viability by the cooperation of nuclear factor (erythroid-derived 2)-like 2 and hypoxia-inducible factor-1α under hypoxic conditions

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Ju-Won Jang ◽  
Pham Xuan Thuy ◽  
Jae-Wook Lee ◽  
Eun-Yi Moon
Keyword(s):  
B Cells ◽  
Cell Viability ◽  
B Cell ◽  
Hypoxia Inducible Factor ◽  
Gene Promoter ◽  
Hypoxic Condition ◽  
Cxcr4 Expression ◽  
Nuclear Factor ◽  
Cell Functions ◽  
Hypoxic Conditions

AbstractB cells that interact with T cells play a role in regulating the defense function by producing antibodies and inflammatory cytokines. C-X-C chemokine receptor type 4 (CXCR4) is a specific receptor for stromal cell-derived factor 1 (SDF-1) that controls various B cell functions. Here, we investigated whether CXCR4 regulates B cell viability by inducing hypoxia-inducible factor (HIF)-1α and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) under a hypoxic condition in WiL2-NS human B cells. Nrf2 and CXCR4 expressions increased significantly when WiL2-NS cells were incubated under a hypoxic condition. Interfering with CXCR4 expression using CXCR4-siRNA inhibited cell viability. CXCR4 expression also decreased after treatment with a HIF inhibitor under the hypoxic condition, leading to inhibited cell viability. Increased reactive oxygen species (ROS) levels and the expression of HIF-1α and Nrf2 decreased under the hypoxic condition following incubation with N-acetylcysteine, a ROS scavenger, which was associated with a decrease in CXCR4 expression. CXCR4 expression was augmented by overexpressing Nrf2 after transfecting the pcDNA3.1-Nrf2 plasmid. CXCR4 expression decreased and HIF-1α accumulation decreased when Nrf2 was inhibited by doxycycline in tet-shNrf2-expressed stable cells. Nrf2 or HIF-1α bound from −718 to −561 of the CXCR4 gene promoter as judged by a chromatin immunoprecipitation assay. Taken together, these data show that B cell viability under a hypoxic condition could be regulated by CXCR4 expression through binding of HIF-1α and Nrf2 to the CXCR4 gene promoter cooperatively. These results suggest that CXCR4 could be an additional therapeutic target to control B cells with roles at disease sites under hypoxic conditions.

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