scholarly journals Mitochondrial O-GlcNAc Transferase Interacts with and Modifies Many Proteins and Its Up-Regulation Affects Mitochondrial Function and Cellular Energy Homeostasis

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2956
Author(s):  
Paweł Jóźwiak ◽  
Piotr Ciesielski ◽  
Piotr K. Zakrzewski ◽  
Karolina Kozal ◽  
Joanna Oracz ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Energy Homeostasis ◽  
Glucose Sensor ◽  
Single Gene ◽  
Mitochondrial Proteins ◽  
Mitochondrial Activity ◽  
Ros Generation ◽  
Inner Mitochondrial Membrane ◽  
Glcnac Transferase ◽  
The Impact

O-GlcNAcylation is a cell glucose sensor. The addition of O-GlcNAc moieties to target protein is catalyzed by the O-Linked N-acetylglucosamine transferase (OGT). OGT is encoded by a single gene that yields differentially spliced OGT isoforms. One of them is targeted to mitochondria (mOGT). Although the impact of O-GlcNAcylation on cancer cells biology is well documented, mOGT’s role remains poorly investigated. We performed studies using breast cancer cells with up-regulated mOGT or its catalytic inactive mutant to identify proteins specifically modified by mOGT. Proteomic approaches included isolation of mOGT protein partners and O-GlcNAcylated proteins from mitochondria-enriched fraction followed by their analysis by mass spectrometry. Moreover, we analyzed the impact of mOGT dysregulation on mitochondrial activity and cellular metabolism using a variety of biochemical assays. We found that mitochondrial OGT expression is glucose-dependent. Elevated mOGT expression affected the mitochondrial transmembrane potential and increased intramitochondrial ROS generation. Moreover, mOGT up-regulation caused a decrease in cellular ATP level. We identified many mitochondrial proteins as mOGT substrates. Most of these proteins are localized in the mitochondrial matrix and the inner mitochondrial membrane and participate in mitochondrial respiration, fatty acid metabolism, transport, translation, apoptosis, and mtDNA processes. Our findings suggest that mOGT interacts with and modifies many mitochondrial proteins, and its dysregulation affects cellular bioenergetics and mitochondria function.

scholarly journals Quercetin and Naringenin Provide Functional and Antioxidant Protection to Stored Boar Semen

Animals ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 1930
Author(s):  
Eva Tvrdá ◽  
Mégane Debacker ◽  
Michal Ďuračka ◽  
Ján Kováč ◽  
Ondřej Bučko
Keyword(s):  
Mitochondrial Activity ◽  
Ros Generation ◽  
Dna Integrity ◽  
Membrane Stabilization ◽  
New Information ◽  
Semen Storage ◽  
Boar Semen ◽  
Boar Spermatozoa ◽  
The Impact ◽  
Sample Dilution

In this study, we evaluated the impact of 5–50 μM quercetin (QUE) and naringenin (NAR) on extended boar spermatozoa in the BTS (Beltsville Thawing Solution) medium for 72 h. Spermatozoa motion, membrane, acrosome, and DNA integrity were investigated immediately after sample dilution (0 h) as well as after 24 h, 48 h, and 72 h of semen storage. Furthermore, reactive oxygen species (ROS) and superoxide production, as well as the extent of oxidative damage to the sperm proteins and lipids, were assessed to determine the potential of QUE and NAR to prevent a potential loss of sperm vitality due to oxidative stress development. Our results indicate that the most notable parameter influenced by QUE was the mitochondrial activity, which remained significantly higher throughout the experiment (p < 0.001 and p < 0.0001; 10 μM), and which correlated with the most prominent maintenance of sperm motility (p < 0.01, 48 h; p < 0.05, 72 h). A significant membrane stabilization (p < 0.01, 24 h and 48 h; p < 0.0001, 72 h) and prevention of lipid peroxidation (p < 0.05, 24 h and 48 h; p < 0.01, 72 h) was primarily observed following administration of 10 and 25 μM NAR; respectively. Administration of 10 μM QUE led to a significant decrease of superoxide (p < 0.0001, 48 h and 72 h) while the most notable decline of ROS generation was recorded in the case of 10 and 25 μM NAR (p < 0.001). This study may provide new information on the specific mechanisms of action involved in the favorable effects of natural biomolecules on spermatozoa.

scholarly journals Extracellular Citrate Fuels Cancer Cell Metabolism and Growth

2020 ◽  
Vol 8 ◽  
Author(s):  
Sebastian Haferkamp ◽  
Konstantin Drexler ◽  
Marianne Federlin ◽  
Hans J. Schlitt ◽  
Mark Berneburg ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Cell Metabolism ◽  
Mitochondrial Activity ◽  
Cancer Cell Proliferation ◽  
Atp Production ◽  
Proliferation And Metastasis ◽  
Cancer Cell Metabolism ◽  
The Impact ◽  
Cell Proliferation And Metastasis

Cancer cells need excess energy and essential nutrients/metabolites not only to divide and proliferate but also to migrate and invade distant organs for metastasis. Fatty acid and cholesterol synthesis, considered a hallmark of cancer for anabolism and membrane biogenesis, requires citrate. We review here potential pathways in which citrate is synthesized and/or supplied to cancer cells and the impact of extracellular citrate on cancer cell metabolism and growth. Cancer cells employ different mechanisms to support mitochondrial activity and citrate synthesis when some of the necessary substrates are missing in the extracellular space. We also discuss the different transport mechanisms available for the entry of extracellular citrate into cancer cells and how citrate as a master metabolite enhances ATP production and fuels anabolic pathways. The available literature suggests that cancer cells show an increased metabolic flexibility with which they tackle changing environmental conditions, a phenomenon crucial for cancer cell proliferation and metastasis.

The Impact of Antioxidants from the Diet on Breast Cancer Cells Monitored by Raman Microspectroscopy

2018 ◽  
Vol 16 (2) ◽  
pp. 127-137
Author(s):  
Paula Sofia Coutinho Medeiros ◽  
Ana Lúcia Marques Batista de Carvalho ◽  
Cristina Ruano ◽  
Juan Carlos Otero ◽  
Maria Paula Matos Marques
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Breast Adenocarcinoma ◽  
Coumaric Acid ◽  
Human Breast ◽  
The Impact

Background: The impact of the ubiquitous dietary phenolic compound p-coumaric acid on human breast cancer cells was assessed, through a multidisciplinary approach: Combined biological assays for cytotoxicity evaluation and biochemical profiling by Raman microspectroscopic analysis in cells. </P><P> Methods: Para-coumaric acid was shown to exert in vitro chemoprotective and antitumor activities, depending on the concentration and cell line probed: a significant anti-invasive ability was detected for the triple-negative MDA-MB-231 cells, while a high pro-oxidant effect was found for the estrogen- dependent MCF-7 cells. A striking cell selectivity was obtained, with a more noticeable outcome on the triple-negative MDA-MB-231 cell line. Results: The main impact on the cellular biochemical profile was verified to be on proteins and lipids, thus justifying the compound´s anti-invasive effect and chemoprotective ability. Conclusion: p-Coumaric acid was thus shown to be a promising chemoprotective/chemotherapeutic agent, particularly against the low prognosis triple-negative human breast adenocarcinoma.

scholarly journals Oxidative Stress in the Tumor Microenvironment and Its Relevance to Cancer Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 986
Author(s):  
Nada S. Aboelella ◽  
Caitlin Brandle ◽  
Timothy Kim ◽  
Zhi-Chun Ding ◽  
Gang Zhou
Keyword(s):  
Oxidative Stress ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Redox Homeostasis ◽  
Tumor Rejection ◽  
Oxygen Species ◽  
Antitumor Effects ◽  
Key Drivers ◽  
Cancer Immunotherapies ◽  
The Impact

It has been well-established that cancer cells are under constant oxidative stress, as reflected by elevated basal level of reactive oxygen species (ROS), due to increased metabolism driven by aberrant cell growth. Cancer cells can adapt to maintain redox homeostasis through a variety of mechanisms. The prevalent perception about ROS is that they are one of the key drivers promoting tumor initiation, progression, metastasis, and drug resistance. Based on this notion, numerous antioxidants that aim to mitigate tumor oxidative stress have been tested for cancer prevention or treatment, although the effectiveness of this strategy has yet to be established. In recent years, it has been increasingly appreciated that ROS have a complex, multifaceted role in the tumor microenvironment (TME), and that tumor redox can be targeted to amplify oxidative stress inside the tumor to cause tumor destruction. Accumulating evidence indicates that cancer immunotherapies can alter tumor redox to intensify tumor oxidative stress, resulting in ROS-dependent tumor rejection. Herein we review the recent progresses regarding the impact of ROS on cancer cells and various immune cells in the TME, and discuss the emerging ROS-modulating strategies that can be used in combination with cancer immunotherapies to achieve enhanced antitumor effects.

scholarly journals A nanoselenium-coating biomimetic cytomembrane nanoplatform for mitochondrial targeted chemotherapy- and chemodynamic therapy through manganese and doxorubicin codelivery

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jianmin Xiao ◽  
Miao Yan ◽  
Ke Zhou ◽  
Hui Chen ◽  
Zhaowei Xu ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Cancer Cells ◽  
High Yield ◽  
Ros Generation ◽  
Superoxide Dismutase 1 ◽  
Nuclear Targeting ◽  
Dual Mode ◽  
Red Cell Membrane ◽  
Cancer Cell Death ◽  
Drug Nanocarriers

Abstract The cell membrane is widely considered as a promising delivery nanocarrier due to its excellent properties. In this study, self-assembled Pseudomonas geniculate cell membranes were prepared with high yield as drug nanocarriers, and named BMMPs. BMMPs showed excellent biosafety, and could be more efficiently internalized by cancer cells than traditional red cell membrane nanocarriers, indicating that BMMPs could deliver more drug into cancer cells. Subsequently, the BMMPs were coated with nanoselenium (Se), and subsequently loaded with Mn2+ ions and doxorubicin (DOX) to fabricate a functional nanoplatform (BMMP-Mn2+/Se/DOX). Notably, in this nanoplatform, Se nanoparticles activated superoxide dismutase-1 (SOD-1) expression and subsequently up-regulated downstream H2O2 levels. Next, the released Mn2+ ions catalyzed H2O2 to highly toxic hydroxyl radicals (·OH), inducing mitochondrial damage. In addition, the BMMP-Mn2+/Se nanoplatform inhibited glutathione peroxidase 4 (GPX4) expression and further accelerated intracellular reactive oxygen species (ROS) generation. Notably, the BMMP-Mn2+/Se/DOX nanoplatform exhibited increased effectiveness in inducing cancer cell death through mitochondrial and nuclear targeting dual-mode therapeutic pathways and showed negligible toxicity to normal organs. Therefore, this nanoplatform may represent a promising drug delivery system for achieving a safe, effective, and accurate cancer therapeutic plan.

scholarly journals Aberrant Bcl-x splicing in cancer: from molecular mechanism to therapeutic modulation

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Zhihui Dou ◽  
Dapeng Zhao ◽  
Xiaohua Chen ◽  
Caipeng Xu ◽  
Xiaodong Jin ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Human Cancer ◽  
Structural Characteristics ◽  
Therapy Resistance ◽  
Regulatory Elements ◽  
Aberrant Splicing ◽  
Clinical Role ◽  
Splicing Isoforms ◽  
The Impact ◽  
Splicing Patterns

AbstractBcl-x pre-mRNA splicing serves as a typical example to study the impact of alternative splicing in the modulation of cell death. Dysregulation of Bcl-x apoptotic isoforms caused by precarious equilibrium splicing is implicated in genesis and development of multiple human diseases, especially cancers. Exploring the mechanism of Bcl-x splicing and regulation has provided insight into the development of drugs that could contribute to sensitivity of cancer cells to death. On this basis, we review the multiple splicing patterns and structural characteristics of Bcl-x. Additionally, we outline the cis-regulatory elements, trans-acting factors as well as epigenetic modifications involved in the splicing regulation of Bcl-x. Furthermore, this review highlights aberrant splicing of Bcl-x involved in apoptosis evade, autophagy, metastasis, and therapy resistance of various cancer cells. Last, emphasis is given to the clinical role of targeting Bcl-x splicing correction in human cancer based on the splice-switching oligonucleotides, small molecular modulators and BH3 mimetics. Thus, it is highlighting significance of aberrant splicing isoforms of Bcl-x as targets for cancer therapy.

scholarly journals MitoQ Is Able to Modulate Apoptosis and Inflammation

2021 ◽  
Vol 22 (9) ◽  
pp. 4753
Author(s):  
Elisa Piscianz ◽  
Alessandra Tesser ◽  
Erika Rimondi ◽  
Elisabetta Melloni ◽  
Claudio Celeghini ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Mevalonate Pathway ◽  
Neuronal Cell ◽  
Reactive Oxygen ◽  
Mitochondrial Activity ◽  
Oxygen Species ◽  
Short Period ◽  
Inflammatory Stimuli ◽  
Apoptosis And Inflammation ◽  
The Impact

Mitoquinone (MitoQ) is a mitochondrial reactive oxygen species scavenger that is characterized by high bioavailability. Prior studies have demonstrated its neuroprotective potential. Indeed, the release of reactive oxygen species due to damage to mitochondrial components plays a pivotal role in the pathogenesis of several neurodegenerative diseases. The present study aimed to examine the impact of the inflammation platform activation on the neuronal cell line (DAOY) treated with specific inflammatory stimuli and whether MitoQ addition can modulate these deregulations. DAOY cells were pre-treated with MitoQ and then stimulated by a blockade of the cholesterol pathway, also called mevalonate pathway, using a statin, mimicking cholesterol deregulation, a common parameter present in some neurodegenerative and autoinflammatory diseases. To verify the role played by MitoQ, we examined the expression of genes involved in the inflammation mechanism and the mitochondrial activity at different time points. In this experimental design, MitoQ showed a protective effect against the blockade of the mevalonate pathway in a short period (12 h) but did not persist for a long time (24 and 48 h). The results obtained highlight the anti-inflammatory properties of MitoQ and open the question about its application as an effective adjuvant for the treatment of the autoinflammatory disease characterized by a cholesterol deregulation pathway that involves mitochondrial homeostasis.

scholarly journals SLC6A8-mediated intracellular creatine accumulation enhances hypoxic breast cancer cell survival via ameliorating oxidative stress

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Qiao Li ◽  
Manran Liu ◽  
Yan Sun ◽  
Ting Jin ◽  
Pengpeng Zhu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Histological Grade ◽  
Metabolic Adaptation ◽  
Mitochondrial Activity ◽  
Cell Viability Assay ◽  
Ki 67 ◽  
The Impact

Abstract Background Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with poor prognosis and limited treatment options. Hypoxia is a key hallmark of TNBC. Metabolic adaptation promotes progression of TNBC cells that are located within the hypoxic tumor regions. However, it is not well understood regarding the precise molecular mechanisms underlying the regulation of metabolic adaptions by hypoxia. Methods RNA sequencing was performed to analyze the gene expression profiles in MDA-MB-231 cell line (20% O2 and 1% O2). Expressions of Slc6a8, which encodes the creatine transporter protein, were detected in breast cancer cells and tissues by quantitative real-time PCR. Immunohistochemistry was performed to detect SLC6A8 protein abundances in tumor tissues. Clinicopathologic correlation and overall survival were evaluated by chi-square test and Kaplan-Meier analysis, respectively. Cell viability assay and flow cytometry analysis with Annexin V/PI double staining were performed to investigate the impact of SLC6A8-mediated uptake of creatine on viability of hypoxic TNBC cells. TNBC orthotopic mouse model was used to evaluate the effects of creatine in vivo. Results SLC6A8 was aberrantly upregulated in TNBC cells in hypoxia. SLC6A8 was drastically overexpressed in TNBC tissues and its level was tightly associated with advanced TNM stage, higher histological grade and worse overall survival of TNBC patients. We found that SLC6A8 was transcriptionally upregulated by p65/NF-κB and mediated accumulation of intracellular creatine in hypoxia. SLC6A8-mediated accumulation of creatine promoted survival and suppressed apoptosis via maintaining redox homeostasis in hypoxic TNBC cells. Furthermore, creatine was required to facilitate tumor growth in xenograft mouse models. Mechanistically, intracellular creatine bolstered cell antioxidant defense by reducing mitochondrial activity and oxygen consumption rates to reduce accumulation of intracellular reactive oxygen species, ultimately activating AKT-ERK signaling, the activation of which protected the viability of hypoxic TNBC cells via mediating the upregulation of Ki-67 and Bcl-2, and the downregulation of Bax and cleaved Caspase-3. Conclusions Our study indicates that SLC6A8-mediated creatine accumulation plays an important role in promoting TNBC progression, and may provide a potential therapeutic strategy option for treatment of SLC6A8 high expressed TNBC.

scholarly journals Seeding of breast cancer cell line (MDA-MB-231LUC+) to the mandible induces overexpression of substance P and CGRP throughout the trigeminal ganglion and widespread peripheral sensory neuropathy throughout all three of its divisions

2021 ◽  
Vol 17 ◽  
pp. 174480692110240
Author(s):  
Silvia Gutierrez ◽  
James C Eisenach ◽  
M Danilo Boada
Keyword(s):  
Breast Cancer ◽  
Substance P ◽  
Cancer Cells ◽  
Cell Line ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Trigeminal Ganglion ◽  
Breast Cancer Cell Line ◽  
Cancer Cell Line ◽  
The Impact

Some types of cancer are commonly associated with intense pain even at the early stages of the disease. The mandible is particularly vulnerable to metastasis from breast cancer, and this process has been studied using a bioluminescent human breast cancer cell line (MDA-MB-231LUC+). Using this cell line and anatomic and neurophysiologic methods in the trigeminal ganglion (TG), we examined the impact of cancer seeding in the mandible on behavioral evidence of hypersensitivity and on trigeminal sensory neurons. Growth of cancer cells seeded to the mandible after arterial injection of the breast cancer cell line in Foxn1 animals (allogeneic model) induced behavioral hypersensitivity to mechanical stimulation of the whisker pad and desensitization of tactile and sensitization of nociceptive mechanically sensitive afferents. These changes were not restricted to the site of metastasis but extended to sensory afferents in all three divisions of the TG, accompanied by widespread overexpression of substance P and CGRP in neurons through the ganglion. Subcutaneous injection of supernatant from the MDA-MB-231LUC+ cell culture in normal animals mimicked some of the changes in mechanically responsive afferents observed with mandibular metastasis. We conclude that released products from these cancer cells in the mandible are critical for the development of cancer-induced pain and that the overall response of the system greatly surpasses these local effects, consistent with the widespread distribution of pain in patients. The mechanisms of neuronal plasticity likely occur in the TG itself and are not restricted to afferents exposed to the metastatic cancer microenvironment.

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