共查询到20条相似文献,搜索用时 31 毫秒
1.
Samuni AM Krishna MC DeGraff W Russo A Planalp RP Brechbiel MW Mitchell JB 《Biochimica et biophysica acta》2002,1571(3):211-218
Tachpyr (N,N'N"-tris(2-pyridylmethyl)-cis,cis-1,3,5-triaminocyclohexane), a novel metal chelator, was previously shown to deplete intracellular iron and exert a cytotoxic effect on cultured bladder cancer cells. Tachpyr binds Fe(II) and readily reduces Fe(III). The iron(II)-Tachpyr chelate undergoes intramolecular oxidative dehydrogenation resulting in mono- and diimino Fe(II) complexes. The present study investigates the redox-activity of the Tachpyr-iron complex to better define the mechanism of Tachpyr's cytotoxicity. Tachpyr's mechanism of cytotoxicity was studied using cell-free solutions, isolated DNA, and cultured mammalian cells by employing UV-VIS spectrophotometry, oximetry, spin-trapping technique, and electron paramagnetic resonance (EPR) spectrometry. The results show that: (1) Tachpyr by itself after 24 h of incubation had a cytotoxic effect on cultured cells; (2) fully oxidized Tachpyr had no cytotoxic effects on cultured cells even after 24 h of incubation; (3) Tachpyr protected isolated DNA against H(2)O(2)-induced damage, but not against HX/XO-induced damage; and (4) Tachpyr-Fe(II) chelate slows down but does not block oxidation of Fe(II), allows O*(-)(2)-induced or Tachpyr-induced reduction of Fe(III), and consequently promotes production of *OH through the Haber-Weiss reaction cycle. The results indicate that Tachpyr can protect cells against short-term, metal-mediated damage. However, upon prolonged incubation, Tachpyr exerts cytotoxic effects. Therefore, in addition to iron depletion, low-level oxidative stress, which in part occurs because of redox cycling of the coordinated iron ion, may contribute to the cytotoxic effects of Tachpyr. 相似文献
2.
Kotamraju S Chitambar CR Kalivendi SV Joseph J Kalyanaraman B 《The Journal of biological chemistry》2002,277(19):17179-17187
In the past, investigators have successfully used iron chelators to mitigate the cardiotoxicity of doxorubicin (DOX), a widely used anticancer drug that induces reactive oxygen species (ROS), oxidative damage, and apoptosis. Although intracellular iron plays a critical role in initiating DOX-induced apoptosis, the molecular mechanism(s) that link iron, ROS, and apoptosis are still unknown. In this study, we demonstrate that apoptosis results from the exposure of bovine aortic endothelial cells to DOX and that the apoptotic cell death is accompanied by a significant increase in cellular iron ((55)Fe) uptake and activation of iron regulatory protein-1. Furthermore, DOX-induced iron uptake was shown to be mediated by the transferrin receptor (TfR)-dependent mechanism. Treatment with the anti-TfR antibody (IgA class) dramatically inhibited DOX-induced apoptosis, iron uptake, and intracellular oxidant formation as measured by fluorescence using dichlorodihydrofluorescein. Treatment with cell-permeable iron chelators and ROS scavengers inhibited DOX-induced cellular (55)Fe uptake, ROS formation, and apoptosis. Based on these findings, we conclude that DOX-induced iron signaling is regulated by the cell surface TfR expression, intracellular oxidant levels, and iron regulatory proteins. The implications of TfR-dependent iron transport in oxidant-induced apoptosis in endothelial cells are discussed. 相似文献
3.
4.
The ability of S. putrefaciens to reduce Fe(III) complexed by a variety of ligands has been investigated. All of the ligands tested caused the cation to be more susceptible to reduction by harvested whole cells than when uncomplexed, although some complexes were more readily reduced than others. Monitoring rates of reduction by a ferrozine assay for Fe(II) formation proved inadequate using Fe(III) ligands giving Fe(II) complexes of low kinetic lability (e.g. EDTA). A more suitable assay for Fe(III) reduction in the presence of such ligands proved to be the observation of associated cytochrome oxidation and re-reduction. Where possible, an assay for Fe(III) reduction based upon the disappearance of Fe(III) complex was also employed. Reduction of all Fe(III) complexes tested was totally inhibited by the presence of O2, partially inhibited by HQNO and slower in the absence of a physiological electron donor. Upon cell fractionation, Fe(III) reductase activity was detected exclusively in the membranes. Using different physiological electron donors in assays on membranes, relative reduction rates of Fe(III) complexes complemented the data from whole cells. The differences in susceptibility to reduction of the various complexes are discussed, as is evidence for the respiratory nature of the reduction. 相似文献
5.
Ryan J. Graham Adil Mohammad George Liang Qiang Fu Bingyu Kuang Ashli Polanco Yong Suk Lee R. Kenneth Marcus Seongkyu Yoon 《Biotechnology progress》2021,37(5):e3181
Trace metals play a critical role in the development of culture media used for the production of therapeutic proteins. Iron has been shown to enhance the productivity of monoclonal antibodies during Chinese hamster ovary (CHO) cell culture. However, the redox activity and pro-oxidant behavior of iron may also contribute toward the production of reactive oxygen species (ROS). In this work, we aim to clarify the influence of trace iron by examining the relationship between iron supplementation to culture media, mAb productivity and glycosylation, and oxidative stress interplay within the cell. Specifically, we assessed the impacts of iron supplementation on (a) mAb production and glycosylation; (b) mitochondria-generated free hydroxyl radicals (ROS); (c) the cells ability to store energy during oxidative phosphorylation; and (d) mitochondrial iron concentration. Upon the increase of iron at inoculation, CHO cells maintained a capacity to rebound from iron-induced viability lapses during exponential growth phase and improved mAb productivity and increased mAb galactosylation. Fluorescent labeling of the mitochondrial hydroxyl radical showed enhanced environments of oxidative stress upon iron supplementation. Additional labeling of active mitochondria indicated that, despite the enhanced production of ROS in the mitochondria, mitochondrial membrane potential was minimally impacted. By replicating iron treatments during seed train passaging, the CHO cells were observed to adapt to the shock of iron supplementation prior to inoculation. Results from these experiments demonstrate that CHO cells have the capacity to adapt to enhanced environments of oxidative stress and improve mAb productivity and mAb galactosylation with minimal perturbations to cell culture. 相似文献
6.
Iron is essential for the growth and proliferation of cells, as well as for many biological processes that are important for the maintenance and survival of the human body. However, excess iron is associated with the development of cancer and other pathological conditions, due in part to the pro-oxidative nature of iron and its damaging effects on DNA. Current studies suggest that iron depletion may be beneficial for patients that have diseases associated with iron overload or other iron metabolism disorders that may increase the risk for cancer. On the other hand, studies suggest that cancer cells are more vulnerable to the effects of iron depletion and oxidative stress in comparison to normal cells. Therefore, cancer patients might benefit from treatments that alter both iron metabolism and oxidative stress. This review highlights the pro-oxidant effects of iron, the relationship between iron and cancer development, the vulnerabilities of the iron-dependent cancer phenotype, and how these characteristics may be exploited to prevent or treat cancer. 相似文献
7.
Polypyridyl pentadentate ligands N4Py (1) and Bn-TPEN (2), along with their respective iron complexes, have been investigated for their ability to inhibit the purified 20S proteasome. Results demonstrated that the iron complexes of both ligands are potent inhibitors of the 20S proteasome (IC(50) = 9.2 μM for [Fe(II)(OH(2))(N4Py)](2+) (3) and 4.0 μM for [Fe(II)(OH(2))(Bn-TPEN)](2+) (4)). Control experiments showed that ligand 1 or Fe(II) alone showed no inhibition, whereas 2 was moderately active (IC(50) = 96 μM), suggesting that iron, when bound to these ligands, plays a key role in proteasome inhibition. Results from time-dependent inactivation studies suggest different modes of action for the iron complexes. Time-dependent decay of proteasome activity was observed upon incubation in the presence of 4, which accelerated in the presence of DTT, suggesting reductive activation of O(2) and oxidation of the 20S proteasome as a mode of action. In contrast, loss of 20S proteasome activity was not observed with 3 over time, suggesting inhibition through direct binding of the iron complex to the enzyme. Inhibition of the 20S proteasome by 4 was not blocked by reactive oxygen species scavengers, consistent with a unique oxidant being responsible for the time-dependent inhibition observed. 相似文献
8.
Kowol CR Heffeter P Miklos W Gille L Trondl R Cappellacci L Berger W Keppler BK 《Journal of biological inorganic chemistry》2012,17(3):409-423
Intracellular generation of reactive oxygen species (ROS) via thiol-mediated reduction of copper(II) to copper(I) has been
assumed as the major mechanism underlying the anticancer activity of copper(II) complexes. The aim of this study was to compare
the anticancer potential of copper(II) complexes of Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone; currently
in phase II clinical trials) and its terminally dimethylated derivative with that of 2-formylpyridine thiosemicarbazone and
that of 2,2′-bipyridyl-6-carbothioamide. Experiments on generation of oxidative stress and the influence of biologically relevant
reductants (glutathione, ascorbic acid) on the anticancer activity of the copper complexes revealed that reductant-dependent
redox cycling occurred mainly outside the cells, leading to generation and dismutation of superoxide radicals resulting in
cytotoxic amounts of H2O2. However, without extracellular reductants only weak intracellular ROS generation was observed at IC50 levels, suggesting that cellular thiols are not involved in copper-complex-induced oxidative stress. Taken together, thiol-induced
intracellular ROS generation might contribute to the anticancer activity of copper thiosemicarbazone complexes but is not
the determining factor. 相似文献
9.
D Eide S Davis-Kaplan I Jordan D Sipe J Kaplan 《The Journal of biological chemistry》1992,267(29):20774-20781
Iron is required for the growth of Saccharomyces cerevisiae. High concentrations of iron, however, are toxic, forcing this yeast to tightly regulate its concentration of intracellular free iron. We demonstrate that S. cerevisiae accumulates iron through the combined action of a plasma membrane ferrireductase and an Fe(II) transporter. This transporter is highly selective for Fe(II). Several other transition metals did not inhibit iron uptake when these metals were present at a concentration 100-fold higher than the Km (0.15 microM) for iron transport. Pt(II) inhibited ferrireductase activity but not the ability of cells to transport iron that was chemically reduced to Fe(II). Incubation of cells in a synthetic iron-limited media resulted in the induction of both ferrireductase and Fe(II) transporter activities. In complex media, Fe(II) transport activity was regulated in response to media iron concentration, while the activity of the ferrireductase was not. When stationary phase cells were inoculated into fresh media, ferrireductase activity increased independent of the iron content of the media; in contrast, transporter activity varied inversely with iron levels. These results demonstrate that the ferrireductase and Fe(II) transporter are separately regulated and that iron accumulation may be limited by changes in either activity. 相似文献
10.
Yao D Shi W Gou Y Zhou X Yee Aw T Zhou Y Liu Z 《Free radical biology & medicine》2005,39(10):1385-1398
Fatty acid has been reported to be associated with cardiovascular diseases and cancer, but the possible mechanism remains unclear. Here, we reported a novel mechanism for the permissive role of fatty acid on iron intracellular translocation and subsequent oxidative injury. In vitro study from endothelial cells showed that iron alone had little effect, whereas in combination with PA (palmitic acid), iron-mediated toxicity was markedly potentiated, as reflected in mitochondrial dysfunction, cell death, apoptosis, and DNA mutation. We also showed that PA not only facilitated iron translocation into cells through a transferrin-receptor (TfR)-independent mechanism, but also translocated iron into mitochondria; the subsequent intracellular iron overload resulted in reactive oxygen species (ROS) overgeneration and lipid oxidation. Further investigation revealed that PA-facilitated iron translocation is due to Fe/PA-mediated extracellular oxidative stress and the subsequent membrane damage with increased membrane permeability. Fe/PA-mediated toxic effects were reduced in rho0 cells lacking mitochondrial DNA or by antioxidant enzyme SOD, especially mitochondrially localized MnSOD, suggesting a permissive role of PA for iron deposition on the vascular wall and its subsequent toxicity via mitochondrial oxidative stress. This observation was confirmed in vivo in mice, wherein higher vascular iron deposition and accompanying superoxide release were observed in the presence of a high-fat diet with iron administration. 相似文献
11.
Uptake and handling of iron from transferrin, lactoferrin and immune complexes by a macrophage cell line.
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The murine macrophage-like cell line P388D1 has been used as a model to investigate whether iron acquired simultaneously from different sources (transferrin, lactoferrin, and ovotransferrin-anti-ovotransferrin immune complexes) is handled in the same way. P388D1 cells bound both lactoferrin and transferrin, but over a 6 h incubation period only the latter actually donated iron to the cells. When the cells were incubated with [55Fe]transferrin and [59Fe]ovotransferrin-anti-ovotransferrin immune complexes iron was acquired from both sources. However, there was a difference in the intracellular distribution of the two isotopes, proportionally more 55Fe entering haem compounds and less entering ferritin. When the cells were precultured in a low-iron serum-free medium almost no transferrin-iron was incorporated into ferritin, whereas the proportion of immune complex-derived iron incorporated into ferritin was unchanged. Lactoferrin enhanced the rate of cellular proliferation, as measured by [3H]thymidine incorporation, despite its inability to donate iron to the cells, suggesting a stimulatory effect independent of iron donation. In contrast immune complexes inhibited cell proliferation. These findings indicate that iron acquired from transferrin and iron acquired by scavenging mechanisms are handled differently, and suggest that more than one intracellular iron transit pool may exist. 相似文献
12.
Fernanda Augusta de Lima Barbosa Guterres Glaucia Regina MartinezMaria Eliane Merlin Rocha Sheila Maria Brochado Winnischofer 《Experimental cell research》2013
Recent studies demonstrated that simvastatin has antitumor properties in several types of cancer cells, mainly by inducing apoptosis and inhibiting growth. The arrest of proliferation is a feature of cellular senescence; however, the occurrence of senescence in melanoma cells upon simvastatin treatment has not been investigated until now. Our results demonstrated that exposure of human metastatic melanoma cells (WM9) to simvastatin induces a senescent phenotype, characterized by G1 arrest, positive staining for senescence-associated β-galactosidase assay, and morphological changes. Also, the main pathways leading to cell senescence were examined in simvastatin-treated human melanoma cells, and the expression levels of phospho-p53 and p21 were upregulated by simvastatin, suggesting that cell cycle regulators and DNA damage pathways are involved in the onset of senescence. Since simvastatin can act as a pro-oxidant agent, and oxidative stress may be related to senescence, we measured the intracellular ROS levels in WM9 cells upon simvastatin treatment. Interestingly, we found an increased amount of intracellular ROS in these cells, which was accompanied by elevated expression of catalase and peroxiredoxin-1. Collectively, our results demonstrated that simvastatin can induce senescence in human melanoma cells by activation of p53/p21 pathway, and that oxidative stress may be related to this process. 相似文献
13.
Diphenyl diselenide (DPDS) is an electrophilic reagent used in the synthesis of a variety of pharmacologically active organic selenium compounds, and may increase the risk of human exposure to this chemical at the workplace. In a previous study, we demonstrated the pro-oxidant action and the mutagenic properties of this compound on bacteria and yeast. In the present study, we evaluated the putative cytotoxic, pro-oxidant, genotoxic, and mutagenic properties of this molecule in V79 Chinese lung fibroblast cells. When cells were treated with increasing concentrations of DPDS, its cytotoxic activity, as determined using four cell viability endpoints, occurs in doses up to 50 microM. The MTT reduction was stimulated, which may indicate reactive oxygen species (ROS) generation. Accordingly, the treatment of cells for 3h with cytotoxic doses of DPDS increased TBARS levels, and sensitized cells to oxidative challenge, indicating a pro-oxidant effect. The measurement of total, reduced, and oxidized glutathione showed that DPDS can lead to lower intracellular glutathione depletion, with no increase in the oxidation rate in a dose- and time-dependent manner. At the higher doses, DPDS generates DNA strand breaks, as observed using the comet assay. The treatment also induced an increase in the number of binucleated cells in the micronucleus test, showing mutagenic risk by this molecule at high concentrations. Finally, pre-incubation with N-acetylcysteine, which restored GSH to normal levels, annulled DPDS pro-oxidant and genotoxic effects. These findings show that DPDS-induced oxidative stress and toxicity are closely related to intracellular level of reduced glutathione. Moreover, at lower doses, this molecule has antioxidant properties, protecting the cell against oxidative damage induced by hydrogen peroxide. 相似文献
14.
Xiaolin Xu Chenglong Wang Peipei Zhang Xuzhu Gao Wencai Guan Fanchen Wang Xin Li Jia Yuan Hongjing Dou Guoxiong Xu 《International journal of biological sciences》2022,18(1):374
Anti-cancer chemo-drugs can cause a rapid elevation of intracellular reactive oxygen species (ROS) levels. An imbalance in ROS production and elimination systems leads to cancer cell resistance to chemotherapy. This study aimed to evaluate the mechanism and effect of ROS on multidrug resistance in various human chemoresistant cancer cells by detecting the changes in the amount of ROS, the expression of ROS-related and glycolysis-related genes, and cell death. We found that ROS was decreased while oxidative phosphorylation was increased in chemoresistant cells. We verified that the chemoresistance of cancer cells was achieved in two ways. First, chemoresistant cells preferred oxidative phosphorylation instead of anaerobic glycolysis for energy generation, which increased ATPase activity and produced much more ATP to provide energy. Second, ROS-scavenging systems were enhanced in chemoresistant cancer cells, which in turn decreased ROS amount and thus inhibited chemo-induced cell death. Our in vitro and in vivo photodynamic therapy further demonstrated that elevated ROS production efficiently inhibited chemo-drug resistance and promoted chemoresistant cell death. Taken together, targeting ROS systems has a great potential to treat cancer patients with chemoresistance. 相似文献
15.
G. Park F. H. Lu N. Ye M. W. Brechbiel S. V. Torti F. M. Torti R. P. Planalp 《Journal of biological inorganic chemistry》1998,3(5):449-457
The interaction of Fe(II) and Fe(III) with the novel Fe(II) chelator N,N′N″-tris(2-pyridylmethyl)-cis,cis-1,3,5-triaminocyclohexane (referred to as tachpyr) gives rise to six-coordinate, low-spin, cationic complexes of Fe(II).
Tachpyr also displays a cytotoxicity toward cultured bladder cancer cells that is believed to involve coordination of intracellular
iron. The anaerobic reaction of tachpyr with Fe(II) salts affords the Fe(II)-tachpyr2+ complex, but in presence of oxygen, oxidative dehydrogenation of one or two of the aminomethylene group(s) of the ligand
occurs, with formal loss of H2: R—N(H)—C(H)2—(2-py) → R—N=C(H)—(2-py)+H2. The resulting mono- and diimino Fe(II) complexes (denoted as [Fe(tachpyr-H2)]2+ and [Fe(tachpyr-2H2)]2+) are an inseparable mixture, but they may be fully oxidized by H2O2 to the known tris(imino) complex Fe(II)[cis,cis-1,3,5-tris(pyridine-2-carboxaldimino)cyclohexane]2+ (or [Fe(tachpyr-3H2)]2+). Cyclic voltammetry of the imino complex mixture reveals an irreversible anodic wave at +0.78 V vs. NHE. Tachpyr acts as
a reducing agent toward Fe(IIII) salts, affording the same two Fe(II) imino complexes as products. Tachpyr also reductively
removes Fe(III) from an Fe(III)(ATP)3 complex (which is a putative form of intracellular iron), producing the two Fe(II) imino complexes. Novel N-alkylated derivatives of tachpyr have been synthesized. N-Alkylation has two effects on tachpyr: lowering metal affinity through increased steric hindrance, and preventing Fe(III)
reduction because oxidative dehydrogenation of nitrogen is blocked. The N-methyl tachpyr derivative binds Fe(II) only weakly as a high-spin complex, and no complexation or reduction of Fe(III) is
observed. Corresponding to their inability to bind iron, the N-alkylated chelators are nontoxic to cultured bladder cancer cells. A tach-based chelator with three N-propyleneamino arms is also synthesized. Studies of the chemical and biochemical properties of this chelator further support
a relationship between intracellular iron chelation, iron reduction, and cytotoxicity.
Received: 23 March 1998 / Accepted: 1 June 1998 相似文献
16.
《Biochimica et Biophysica Acta (BBA)/General Subjects》2020,1864(3):129503
BackgroundIn recent times, coordination complexes of iron in various oxidation states along with variety of ligand systems have been designed and developed for effective treatment of cancer cells without adversely affecting the normal cell and tissues of various organs.MethodsIn this study, we have evaluated the mechanism of action of a Fe(II) Schiff base complex in the crop plant Trigonella foenum-graecum L. (Fenugreek) as the screening system by using morphological, cytological, biochemical and molecular approaches. Further functional characterization was performed using MCF-7 cell line and solid tumour model for the assessment of anti-tumour activity of the complex.ResultsOur results indicate efficiency of the Fe(II) Schiff base complex in the induction of double strand breaks in DNA. Complex treatment clearly induced cytotoxic and genotoxic damage in Trigonella seedlings. The Fe-complex treatment caused cell cycle arrest via the activation of ATM-ATR kinase mediated DNA damage response pathway with the compromised expression of CDK1, CDK2 and CyclinB1 protein in Trigonella seedlings. In cultured MCF-7 cells, the complex induces cytotoxicity and DNA fragmentation through intracellular ROS generation. Fe-complex treatment inhibited tumour growth in solid tumour model with no additional side effects.ConclusionThe growth inhibitory and cytotoxic effects of the complex result from activation of DNA damage response along with oxidative stress and cell cycle arrest.General significanceOverall, our results have provided comprehensive information on the mechanism of action and efficacy of a Fe(II) Schiff base complex in higher eukaryotic genomes and indicated its future implications as potential therapeutic agent. 相似文献
17.
Jung Im Lee Chang-Suk Kong Myoung Eun Jung Joo Wan Hong Sun Young Lim Youngwan Seo 《Biotechnology and Bioprocess Engineering》2011,16(5):992-999
In this study, the antioxidant potentials of crude extracts and solvent-partitioned fractions of Limonium tetragonum were assessed by measuring their ability to scavenge intracellular reactive oxygen species (ROS) generated in HT-1080 cells. Following activity-oriented separation, four flavonol glycosides were isolated as active principles and their chemical structures were determined by 2 D NMR and by comparison with reported spectral data. The isolated compounds (1?C4) were evaluated for their antioxidant capacity using three different activity tests; degree of occurrence of intracellular ROS, lipid peroxidation in HT-1080 cells and the extent of oxidative damage of genomic DNA purified from HT-1080 cells. All compounds exhibited significantly inhibited the generation of intracellular ROS and lipid peroxidation in HT-1080 cells, and significantly inhibited DNA oxidation. In addition, direct free radical scavenging effects of these compounds were investigated using the electron spin resonance (ESR) spin-trap technique. 相似文献
18.
Edwards SE Loder CS Wu G Corker H Bainbridge BW Hill S Poole RK 《FEMS microbiology letters》2000,191(1):71-77
Azotobacter vinelandii cydAB mutants lacking cytochrome bd lost viability in stationary phase, irrespective of temperature, but microaerobiosis or iron addition to stationary phase cultures prevented viability loss. Growth on solid medium was inhibited by a diffusible factor from neighbouring cells, and by iron chelators, In(III) or Ga(III); microaerobic growth overcame inhibition by the extracellular factor. Siderophore production and total Fe(III)-chelating activity were not markedly affected in Cyd(-) mutants, and remained responsive to iron repression. Cyd(-) mutants were hypersensitive to Cu(II), Zn(II), and compounds exerting oxidative stress. Failure to synthesise haemoproteins does not explain the complex phenotype since mutants retained significant catalase activity. We hypothesise that Cyd(-) mutants are defective in maintaining the near-anoxic cytoplasm required for reductive iron metabolism and nitrogenase activity. 相似文献
19.
This work is a part of a directional search for new crystal donors of nitric oxide (NO), which are promising for complex chemotherapy. The relationships between the physico-chemical properties of NO donors, their genotoxic and mutagenic activities, and the dependence on intracellular iron were studied. New crystal NO donors (di- and trinitrosyl iron complexes with synthetic ligands) were examined for the first time and compared with known NO donors containing natural ligands. All but one compound induced expression of the Escherichia coli sfiA gene belonging to the SOS regulon and exerted a mutagenic effect on Salmonella typhimurium TA1535. These effects were fully or significantly inhibited by the iron(II)-chelating agent o-phenanthrolin, depending on the mono- or binuclear structure of the ligands. The rate of donating free NO in solution did not positively correlate with the genotoxic activity of the crystal NO donors. The genetic activity of all NO donors proved to depend on intracellular iron. 相似文献
20.
Chatchawan Singhapol Deepali Pal Rafal Czapiewski Mahendar Porika Glyn Nelson Gabriele C. Saretzki 《PloS one》2013,8(1)
Most cancer cells express high levels of telomerase and proliferate indefinitely. In addition to its telomere maintenance function, telomerase also has a pro-survival function resulting in an increased resistance against DNA damage and decreased apoptosis induction. However, the molecular mechanisms for this protective function remain elusive and it is unclear whether it is connected to telomere maintenance or is rather a non-telomeric function of the telomerase protein, TERT. It was shown recently that the protein subunit of telomerase can shuttle from the nucleus to the mitochondria upon oxidative stress where it protects mitochondrial function and decreases intracellular oxidative stress. Here we show that endogenous telomerase (TERT protein) shuttles from the nucleus into mitochondria upon oxidative stress in cancer cells and analyzed the nuclear exclusion patterns of endogenous telomerase after treatment with hydrogen peroxide in different cell lines. Cell populations excluded TERT from the nucleus upon oxidative stress in a heterogeneous fashion. We found a significant correlation between nuclear localization of telomerase and high DNA damage, while cells which excluded telomerase from the nucleus displayed no or very low DNA damage. We modeled nuclear and mitochondrial telomerase using organelle specific localization vectors and confirmed that mitochondrial localization of telomerase protects the nucleus from inflicted DNA damage and apoptosis while, in contrast, nuclear localization of telomerase correlated with higher amounts of DNA damage and apoptosis. It is known that nuclear DNA damage can be caused by mitochondrially generated reactive oxygen species (ROS). We demonstrate here that mitochondrial localization of telomerase specifically prevents nuclear DNA damage by decreasing levels of mitochondrial ROS. We suggest that this decrease of oxidative stress might be a possible cause for high stress resistance of cancer cells and could be especially important for cancer stem cells. 相似文献