Resistance of Ovarian Cancer Cells to Platinum Requires Exogenous Cholesterol, Scavenger Receptor Class B Type 1, and Glutathione Peroxidase 4
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA981189 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24870908.fastq.gz | Fastqsanger.gz | |||
| SRR24870909.fastq.gz | Fastqsanger.gz | |||
| SRR24870910.fastq.gz | Fastqsanger.gz | |||
| SRR24870911.fastq.gz | Fastqsanger.gz | |||
| SRR24870912.fastq.gz | Fastqsanger.gz |
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Project description:Essentially, all patients diagnosed with ovarian cancer (OC) are treated with platinum (Pt); however, Pt resistance (Pt-R) rapidly develops. We show OC cells resistant to Pt increase intracellular cholesterol by increasing expression of the high-density lipoprotein (HDL) receptor, scavenger receptor class B type 1 (SR-B1). Expression of SR-B1 was associated with chemoresistance in OC cells and tumors. SR-B1 blockade using synthetic cholesterol-poor HDL-like nanoparticles (HDL NPs) diminished cholesterol uptake leading to cell death of Pt-R OC cells in vitro and suppressed Pt-R OC tumor growth in vivo. Reduced cholesterol accumulation in Pt-R OC cells induced lipid oxidative stress through reduction of glutathione peroxidase 4 (GPx4) expression leading to ferroptosis. Reduction of GPx4 expression in OC cells re-sensitized Pt-R cells to Pt by reducing cholesterol uptake and enhancing the accumulation of lipid reactive oxygen species (L-ROS). Mechanistically, GPx4 knockdown in OC cells was associated with reduced expression of the histone acetyltransferase EP300, leading to reduced H3K27 acetylation around the SREBP2 promoter suppressing its expression. As SREBP2 regulates SR-B1 transcription, these data demonstrate chemoresistance and cancer cell survival under high ROS burden obligates high GPx4 and SR-B1 expression through SREBP2. Targeting SR-B1 to modulate cholesterol uptake inhibits this axis and causes ferroptosis in vitro and in vivo in Pt-R OC.
2024-06-01 | GSE234404 | GEO
Project description:Native protein extracts from 2-week-old seedlings of wild-type and GPX1-OE lines were used to identify interactions partners of glutathione peroxidase 1 in rice.
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Project description:Global analyses on gene expression profiles in two soybean species, Nanahomare and Tamahomare was performed using DNA microarray technique. Nanahomare is glycinin deficient species, and is high in free amino acid content. Tamahomare is parent species of Nanahomare. In Nanahomare, stress related genes glutathione S-transferase and ascorbate peroxidase had higher expression than in Tamahomare, which suggests glycinin-deficiency caused stress in soy seeds, and that it lead Nanahomare to increase in free amino acid content. Keywords: storage protein deficiency
2010-06-04 | GSE22158 | GEO
Project description:Glutathione plays a tremendous role in regulating the homeostasis of redox state, and appears to be essential for proper development of the root nodules. Glutathione peroxidase catalyzes the reduction of peroxides by oxidation of GSH to oxidized GSH (GSSG), which can in turn be reduced by glutathione reductase (GR). However, it has not been determined whether the R. leguminosarum Gpx or GR is required during symbiotic interactions with pea. To characterise the role of glutathione-dependent enzymes in the symbiotic process, single and double mutants were made in gpxA and gorA genes. All the mutations did not affect the growth of R. leguminosarum, but they increased the sensitivity of R. leguminosarum strains to H2O2. The gorA mutant can induce the formation of normal nodules, while the gpxA single and double mutants exhibited an abnormal nodulation phenotype coupled to more than 50% reduction in nitrogen-fifixing capacity, this defect in nodulation was characterized by the formation of undeveloped and ineffective nodules. In addition, the gorA and gpxA double mutant was severely impaired in rhizosphere colonization. LC-MS/MS analysis quantitative proteomics techniques were employed to compare differential gpxA mutant root bacteroids in response to the wild type infection. Sixty differentially expressed proteins were identified including seven up-regulated and twenty down-regulated proteins. By sorting the down-regulated proteins according to metabolic function, eight proteins were transporter protein, seven proteins were dehydrogenases and deoxygenases. Moreover, three down-regulation proteins are directly involved in nodule process.
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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: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 | PXD019571 | Pride
Project description:BackgroundPlatinum-based chemotherapy is effective in inducing shrinkage of primary lung cancer lesions; however, it shows finite therapeutic efficacy in patients suffering from brain metastasis (BM). The intrinsic changes of BM cells, which contribute to the poor results remain unknown.MethodsPlatinum drug-sensitivity was assessed by utilizing a preclinical BM model of PC9 lung adenocarcinoma cells in vitro and in vivo. High consumption of glutathione (GSH) and two associated upregulated proteins (GPX4 and GSTM1) in BM were identified by integrated metabolomics and proteomics in cell lines and verified by clinical serum sample. Gain-of-function and rescue experiments were implemented to reveal the impact and mechanism of GPX4 and GSTM1 on the chemosensitivity in BM. The interaction between GPX4 and GSTM1 was examined by immunoblotting and immunoprecipitation. The mechanism of upregulation of GPX4 was further uncovered by luciferase reporter assay, immunoprecipitation, and electrophoretic mobility shift assay.ResultsThe derivative brain metastatic subpopulations (PC9-BrMs) of parental cells PC9 developed obvious resistance to platinum. Radically altered profiles of BM metabolism and protein expression compared with primary lung cancer cells were described and GPX4 and GSTM1 were identified as being responsible for the high consumption of GSH, leading to decreased chemosensitivity by negatively regulating ferroptosis. Besides, GSTM1 was found regulated by GPX4, which was transcriptionally activated by the Wnt/NR2F2 signaling axis in BM.ConclusionsCollectively, our findings demonstrated that Wnt/NR2F2/GPX4 promoted acquired chemoresistance by suppressing ferroptosis with high consumption of GSH. GPX4 inhibitor was found to augment the anticancer effect of platinum drugs in lung cancer BM, providing novel strategies for lung cancer patients with BM.
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Project description:Micro- and nanoplastics (MNPs) are emerging environmental contaminants increasingly detected in human tissues. However, how MNP-related effector mechanisms that impact the immunological function of macrophages remain elusive. Here, we demonstrated that MNPs disrupt redox homeostasis and induce immune dysfunction in bone marrow-derived macrophages. MNP internalization in macrophages impairs mitochondrial function, inducing excessive and sustained production of reactive oxygen species along with suppressed glutathione metabolism, including the substantial down-regulation of key antioxidant enzymes, such as glutathione peroxidase (GPX) 1, GPX3, and GPX4. These processes cause oxidative imbalance, thereby triggering ferroptosis, compromising cellular integrity, and amplifying inflammatory signaling. Two-photon intravital and three-dimensional imaging in mice confirmed that orally administered MNPs accumulate in multiple organs. Such MNP accumulation exacerbates lung tumor progression, potentially through chronic inflammation and the immune dysregulation of macrophages. These findings reveal a novel mechanism by which MNPs alter innate immunity and promote an inflammatory microenvironment via redox-mediated ferroptosis.
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Project description:Renal oncocytomas are rare benign tumors of the kidney and are characterized by a deficient complex I (CI) enzyme activity of the oxidative phosphorylation (OXPHOS) system caused by mitochondrial DNA (mtDNA) mutations. Yet, little is known about the underlying molecular mechanisms and alterations of metabolic pathways in this tumor. We compared renal oncocytomas with adjacent matched normal kidney tissues on a global scale by multi-omics approaches, including whole exome sequencing (WES), proteomics, metabolomics, and metabolic pathway simulation. The abundance of proteins localized to mitochondria increased more than 2-fold, the only exception was a strong decrease in the abundance for CI subunits that revealed multiple pathogenic heteroplasmic mtDNA mutations by WES. We also observed renal oncocytomas to dysregulate main metabolic pathways, shunting away from gluconeogenesis and lipid metabolism. Nevertheless, the abundance of energy carrier molecules such as of NAD+, NADH, NADP, ATP and ADP were significantly higher in renal oncocytoma. Finally, a tremendous 5000-fold increase of the reactive oxygen species (ROS) scavenger glutathione (GSH) can be regarded as a new hallmark of renal oncocytoma. Our findings demonstrate that renal oncocytomas undergo a metabolic switch to eliminate ATP consuming processes to ensure a sufficient energy supply for the tumor.
2017-11-21 | PXD007633 | Pride