Nitric Oxide-releasing prodrug triggers cancer cell death through deregulation of cellular redox balance
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Robert Cheng
PROVIDER: E-GEOD-42344 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:JS-K, a NO donor which capable to induce cancer apopotosis, it's killing mechanism was investigated in this study. We found out that JS-K induce apopotosis via deregulating the GSH/GSSG redox couple.
2012-11-17 | GSE42344 | GEO
Project description:JS-K is a nitric oxide (NO)-releasing prodrug of the O (2)-arylated diazeniumdiolate family that has demonstrated pronounced cytotoxicity and antitumor properties in a variety of cancer models both in vitro and in vivo. The current study of the metabolic actions of JS-K was undertaken to investigate mechanisms of its cytotoxicity. Consistent with model chemical reactions, the activating step in the metabolism of JS-K in the cell is the dearylation of the diazeniumdiolate by glutathione (GSH) via a nucleophilic aromatic substitution reaction. The resulting product (CEP/NO anion) spontaneously hydrolyzes, releasing two equivalents of NO. The GSH/GSSG redox couple is considered to be the major redox buffer of the cell, helping maintain a reducing environment under basal conditions. We have quantified the effects of JS-K on cellular GSH content, and show that JS-K markedly depletes GSH, due to JS-K's rapid uptake and cascading release of NO and reactive nitrogen species. The depletion of GSH results in alterations in the redox potential of the cellular environment, initiating MAPK stress signaling pathways, and inducing apoptosis. Microarray analysis confirmed signaling gene changes at the transcriptional level and revealed alteration in the expression of several genes crucial for maintenance of cellular redox homeostasis, as well as cell proliferation and survival, including MYC. Pre-treating cells with the known GSH precursor and nucleophilic reducing agent N-acetylcysteine prevented the signaling events that lead to apoptosis. These data indicate that multiplicative depletion of the reduced glutathione pool and deregulation of intracellular redox balance are important initial steps in the mechanism of JS-K's cytotoxic action.
| S-EPMC3757670 | biostudies-literature
Project description:Reduced glutathione (GSH) is required for cell cycle initiation and auxin-regulated root meristem development. Transcriptome profiling of the roots and shoots of the root meristemless 1 (rml1) mutant, which has about 3% of the wild type GSH, revealed a divergent auxin and strigolactone response linked to the arrest of the cell cycle. Plants of the rml1 mutant and Columbia-0 ecotype were harvested and separated into roots and shoots, then RNA extraction and Affymetrix Agronomics Tiling Array were performed.
2013-01-10 | E-GEOD-36893 | biostudies-arrayexpress
Project description:Reduced glutathione (GSH) is required for cell cycle initiation and auxin-regulated root meristem development. Transcriptome profiling of the roots and shoots of the root meristemless 1 (rml1) mutant, which has about 3% of the wild type GSH, revealed a divergent auxin and strigolactone response linked to the arrest of the cell cycle.
2013-01-10 | GSE36893 | GEO
Project description:Platinum-based chemotherapy is effective in inducing shrinkage of primary lung cancer lesions; however, it shows limited therapeutic efficacy in patients with brain metastasis (BM). In this study, we utilized a BM model of PC9 lung adenocarcinoma cells and found that the derivative brain metastatic subpopulations (PC9-BrMs) of parental cells PC9 developed obvious resistance to platinum; this suggested that the acquisition of chemo-resistance by brain metastatic cells is attributable to the intrinsic changes in the metastatic cells. Therefore, we performed an integrated profiling of metabolomics and proteomics, and described a radically altered spectrum of BM metabolism and protein expression compared with primary lung cancer cells. We identified a unique metabolite status characterized by high consumption of glutathione (GSH) for antioxidant stress response, both in BM cells and clinical serum samples.
2022-02-15 | PXD019638 | Pride
Project description:Joubert syndrome (JS) is a recessively inherited congenital ataxia characterized by hypotonia, psychomotor delay, abnormal ocular movements, intellectual disability and a peculiar cerebellar and brainstem malformation, the ’molar tooth sign’. Over 40 causative genes have been reported, all encoding for proteins implicated in the structure or functioning of the primary cilium, a subcellular organelle widely present in embryonic and adult tissues. In this paper we developed an in vitro neuronal differentiation model using patient-derived induced pluripotent stem cells (iPSCs), to evaluate possible neurodevelopmental defects in JS. To this end, iPSCs from four JS patients harboring mutations in distinct JS genes (AHI1, CPLANE1, TMEM67 and CC2D2A) were differentiated alongside healthy control cells to obtain mid-hindbrain precursors and cerebellar granule cells. Differentiation was monitored over 31 days through the detection of lineage-specific marker expression by qRT-PCR, immunofluorescence, and transcriptomics analysis. All JS patient-derived iPSCs, regardless of the mutant gene, showed a similar impairment to differentiate into mid-hindbrain and cerebellar granule cells when compared to healthy controls. In addition, analysis of primary cilium count and morphology showed notable ciliary defects in all differentiating JS patient-derived iPSCs compared to controls. These results confirm that patient-derived iPSCs are an accessible and relevant in vitro model to analyze cellular phenotypes connected to the presence of JS gene mutations in a neuronal context.
2024-02-08 | GSE254556 | GEO
Project description:An excess of reactive oxygen species (ROS) can cause severe oxidative damage to cellular components in photosynthetic cells. Antioxidant systems, such as the ascorbate-glutathione cycle, regulate redox status in cells to guard against such damage. Dehydroascorbate reductase (DHAR, EC 1.8.5.1) catalyzes the glutathione-dependent reduction of oxidized ascorbate (dehydroascorbate) and contains a redox active site and glutathione binding-site. The DHAR gene is important in biological and abiotic stress responses involving reduction of the oxidative damage caused by ROS. In this study, a transgenic microalgae (TA) strain was constructed by cloning the Oryza sativa L. japonica DHAR (OsDHAR) gene controlled by an isopropyl β-D-1-thiogalactopyranoside (IPTG)-inducible promoter (Ptrc) into the Synechococcus elongatus PCC 7942 strain of cyanobacteria to study the functional activities of OsDHAR under oxidative stress caused by hydrogen peroxide exposure. OsDHAR expression increased the growth of S. elongatus PCC 7942 under oxidative stress by reducing the levels of hydroperoxides and malondialdehyde (MDA) and mitigating the loss of chlorophyll. DHAR and glutathione S-transferase activity were higher than in the wild-type (WT) strain. Additionally, overexpression of OsDHAR in S. elongatus PCC 7942 greatly increased the glutathione (GSH)/glutathione disulfide (GSSG) ratio compared to ascorbic acid (AsA)/dehydroascorbate (DHA) ratio in the presence or absence of hydrogen peroxide. These results strongly suggest that DHAR attenuates deleterious oxidative effects via the glutathione (GSH)-dependent antioxidant system in cyanobacterial cells. The expression of heterologous OsDHAR in S. elongatus PCC 7942 protected cells from oxidative damage through a GSH-dependent antioxidant system via GSH-dependent reactions at the redox active site and GSH binding site residues during oxidative stress.
2019-11-25 | GSE140121 | GEO
Project description:To find out the binding partners of EhRacM, crosslinking and coimmunoprecipitation were performed. Then, eluted samples were submitted to Mass Spectrometry and Proteomics Core Facility, Johns Hopkins University School of Medicine and analyzed by mass spctrometry (shotgun proteomics). The coimmunoprecipitation and following analysis were conducted three times.You can find the data of HA-EhRacM (1st) from "2022_7_32_54_PM_FileSize_500998639_Byte_F010303.mzid.gz", "2022_7_32_54_PM_FileSize_500998639_Byte_F010303.mzid_2022_7_32_54_PM_File_Size__500998639__Byte__F010303.MGF", "RO-CS-LE_220912_NozakiT_MS_Rac16_WT.mzML", and "RO-CS-LE_220912_NozakiT_MS_Rac16_WT.RAW". You can find the data of pEhExHA (mock) (1st) from "2022_5_02_01_AM_FileSize_662636563_Byte_F010297.mzid.gz", "2022_5_02_01_AM_FileSize_662636563_Byte_F010297.mzid_2022_5_02_01_AM_File_Size__662636563__Byte__F010297.MGF", "RO-CS-LE_220912_NozakiT_MS_pEhExHA.mzML", and "RO-CS-LE_220912_NozakiT_MS_pEhExHA.RAW".You can find the data of HA-EhRacM (2nd) from "2022_7_35_46_AM_FileSize_794949236_Byte_F009769.mzid.gz", "2022_7_35_46_AM_FileSize_794949236_Byte_F009769.mzid_2022_7_35_46_AM_File_Size__794949236__Byte__F009769.MGF", "JS-QE-CS_221108_NozakiT_MS_S1_RA.msf", "JS-QE-CS_221108_NozakiT_MS_S1_RA.RAW", "JS-QE-CS_221108_NozakiT_MS_S1_RA.mzML". You can find the data of pEhExHA (mock) (2nd) from "2022_2_58_28_AM_FileSize_846222756_Byte_F009771.mzid.gz", "2022_2_58_28_AM_FileSize_846222756_Byte_F009771.mzid_2022_2_58_28_AM_File_Size__846222756__Byte__F009771.MGF", "JS-QE-CS_221108_NozakiT_MS_S4_RA.msf", "JS-QE-CS_221108_NozakiT_MS_S4_RA.RAW", and "JS-QE-CS_221108_NozakiT_MS_S4_RA.mzML". You can find the data of HA-EhRacM (3rd) from "2023_12_15_11_AM_FileSize_1380630557_Byte_F012916.mzid.gz", "2023_12_15_11_AM_FileSize_1380630557_Byte_F012916.mzid_2023_12_15_11_AM_File_Size__1380630557__Byte__F012916.MGF", "JS-E480-CS_230518_NozakiT_MS_S1_DDA_10pct.msf", "JS-E480-CS_230518_NozakiT_MS_S1_DDA_10pct.mzML", and "JS-E480-CS_230518_NozakiT_MS_S1_DDA_10pct.RAW". You can find the data of pEhExHA (mock) (3rd) from "2023_6_35_51_PM_FileSize_1732075728_Byte_F012915.mzid.gz", "2023_6_35_51_PM_FileSize_1732075728_Byte_F012915.mzid_2023_6_35_51_PM_File_Size__1732075728__Byte__F012915.MGF", "JS-E480-CS_230518_NozakiT_MS_S4_DDA_10pct.msf", "JS-E480-CS_230518_NozakiT_MS_S4_DDA_10pct.mzML", and "JS-E480-CS_230518_NozakiT_MS_S4_DDA_10pct.RAW".
2024-06-20 | PXD042282 | Pride
Project description:To find out the binding partners of EhRacJ, crosslinking and coimmunoprecipitation were performed. Then, eluted samples were submitted to Mass Spectrometry and Proteomics Core Facility, Johns Hopkins University School of Medicine and analyzed by mass spctrometry (shotgun proteomics). The coimmunoprecipitation and following analysis were conducted only a single time. You can find data of HA-EhRacJ from "2023_3_13_28_AM_FileSize_1261863517_Byte_F012933.mzid.gz", "2023_3_13_28_AM_FileSize_1261863517_Byte_F012933.mzid_2023_3_13_28_AM_File_Size__1261863517__Byte__F012933.MGF", "JS-E480-CS_230524_NozakiT_MS_DDA_S1_10pct.msf", "JS-E480-CS_230524_NozakiT_MS_DDA_S1_10pct.mzML", and "JS-E480-CS_230524_NozakiT_MS_DDA_S1_10pct.RAW". You can find data of pEhEx-HA (mock) from "2023_6_54_27_PM_FileSize_1168419053_Byte_F012936.mzid.gz", "2023_6_54_27_PM_File Size_1168419053_Byte_F012936.mzid_2023_6_54_27_PM_File_Size__1168419053__Byte__F012936.MGF", "JS-E480-CS_230524_NozakiT_MS_DDA_S4_10pct.msf", "JS-E480-CS_230524_NozakiT_MS_DDA_S4_10pct.mzML", and "JS-E480-CS_230524_NozakiT_MS_DDA_S4_10pct.RAW".
2024-06-20 | PXD051913 | Pride
Project description:While it is generally accepted that mitochondrial reactive oxygen species (ROS) balance depends on the both rate of single electron reduction of O2 to superoxide (O2.-) by the electron transport chain and the rate of scavenging by intracellular antioxidant pathways, considerable controversy exists regarding the conditions leading to oxidative stress in intact cells versus isolated mitochondria. Here, we postulate that mitochondria have been evolutionarily optimized to maximize energy output while keeping ROS overflow to a minimum by operating in an intermediate redox state. We show that at the extremes of reduction or oxidation of the redox couples involved in electron transport (NADH/NAD+) or ROS scavenging (NADPH/NADP+, GSH/GSSG), respectively, ROS balance is lost. This results in a net overflow of ROS that increases as one moves farther away from the optimal redox potential. At more reduced mitochondrial redox potentials, ROS production exceeds scavenging, while under more oxidizing conditions (e.g., at higher workloads) antioxidant defenses can be compromised and eventually overwhelmed. Experimental support for this hypothesis is provided in both cardiomyocytes and in isolated mitochondria from guinea pig hearts. The model reconciles, within a single framework, observations that isolated mitochondria tend to display increased oxidative stress at high reduction potentials (and high mitochondrial membrane potential, Psim), whereas intact cardiac cells can display oxidative stress either when mitochondria become more uncoupled (i.e., low Psim) or when mitochondria are maximally reduced (as in ischemia or hypoxia). The continuum described by the model has the potential to account for many disparate experimental observations and also provides a rationale for graded physiological ROS signaling at redox potentials near the minimum.
| S-EPMC2891851 | biostudies-literature