Thioxotriazole copper(II) complex A0 kills cancer cells inducing endoplasmic reticulum stress and paraptotic cell death
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE16247 | GEO | 2009/07/06
SECONDARY ACCESSION(S): PRJNA115185
REPOSITORIES: GEO
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Project description:The unfolded protein response (UPR) is a cellular defense mechanism against glucose deprivation, a cell condition that occurs in solid tumors. A key feature of the UPR is the activation of the transcription program that allows the cell to cope with endoplasmic reticulum (ER) stress. We used micoarrays to show that the UPR transcription program is disrupted by the antitumor macrocyclic compound versipelostatin (VST) and antidiabetic biguanides metformin, buformin and phenformin, depending on cellular glucose availability. Experiment Overall Design: Total 42 samples were prepared for RNA extraction and hybridization on Affymetrix microarrays. Experiment Overall Design: To induce the UPR, we treated cells (HeLa, HT-29, HT1080, MKN74) for 15 or 18 hours under ER stress conditions by replacing the medium with glucose-free medium or by adding either 2-Deoxy-D-glucose (2DG) or Tunicamycin (TM) to glucose-containing medium. UPR modulators (VST, biguanides or pyrvinium pamoate) were added at various final concentrations immediately after cells were placed in glucose-free medium or just before the chemical stressors were added to glucose-containing culture medium.
2009-06-01 | E-GEOD-13548 | biostudies-arrayexpress
Project description:BackgroundsPiperlongumine, a natural plant product, kills multiple cancer types with little effect on normal cells. Piperlongumine raises intracellular levels of reactive oxygen species (ROS), a phenomenon that may underlie the cancer-cell killing. Although these findings suggest that piperlongumine could be useful for treating cancers, the mechanism by which the drug selectively kills cancer cells remains unknown.MethodsWe treated multiple high-grade glioma (HGG) sphere cultures with piperlongumine and assessed its effects on ROS and cell-growth levels as well as changes in downstream signaling. We also examined the levels of putative piperlongumine targets and their roles in HGG cell growth.ResultsPiperlongumine treatment increased ROS levels and preferentially killed HGG cells with little effect in normal brain cells. Piperlongumine reportedly increases ROS levels after interactions with several redox regulators. We found that HGG cells expressed higher levels of the putative piperlongumine targets than did normal neural stem cells (NSCs). Furthermore, piperlongumine treatment in HGG cells, but not in normal NSCs, increased oxidative inactivation of peroxiredoxin 4 (PRDX4), an ROS-reducing enzyme that is overexpressed in HGGs and facilitates proper protein folding in the endoplasmic reticulum (ER). Moreover, piperlongumine exacerbated intracellular ER stress, an effect that was mimicked by suppressing PRDX4 expression.ConclusionsOur results reveal that the mechanism by which piperlongumine preferentially kills HGG cells involves PRDX4 inactivation, thereby inducing ER stress. Therefore, piperlongumine treatment could be considered as a novel therapeutic option for HGG treatment.
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Project description:Ophiobolin A (OP-A), a fungal sesterterpene from Bipolaris oryzae, was recently shown to have anti-glioma activity. We show here that OP-A induces paraptosis-like cell death accompanied by dilation of the endoplasmic reticulum (ER) in glioma cells, and that CHOP-mediated ER stress plays a critical role in this process. OP-A-induced ER-derived dilation and cell death were found to be independent of reactive oxygen species, but were effectively blocked by various thiol antioxidants. We observed that OP-A can react with cysteinyl thiols to form Michael adducts, suggesting that the ability of OP-A to covalently modify free sulfhydryl groups on proteins may cause protein misfolding and the accumulation of misfolded proteins, leading to paraptosis-like cell death. Taken together, these results indicate that the disruption of thiol proteostasis may critically contribute to the anti-glioma activity of OP-A.
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Project description:This experiment compares mRNA expression in cells with and without mitochondrial DNA (M-OM-^A+ and M-OM-^A0 cells respectively). We used global RNA profiling to measure mRNA expression in M-OM-^A+ and M-OM-^A0 cells harvested at log phase from synthetic medium with glucose (CM + 2% glucose, "CMD"), and at 4 hours after transfer to the same medium without glucose (CM). This profiling provided new clues about the ways in which nutirent signaling is reprogrammed in cells lacking mitocondrial DNA. mRNA expression was assessed by analyzing the RNA from three biological replicates obtained under four conditions: M-OM-^A+ cells in glucose, M-OM-^A+ cells no glucose, M-OM-^A0 cells in glucose, M-OM-^A0 cells no glucose.
2013-12-31 | E-GEOD-49002 | biostudies-arrayexpress
Project description:The study of macroalgae capacity to acclimate and recover in environments contaminated with Cu and Cd could prove a promising way to understand the tolerance mechanisms of these seaweeds against different pollutants. This study used as a model organism Gracilaria tenuistipitata (Rhodophyta), a macroalga with economic and ecological importance. The partial transcriptome of G. tenuistipitata was profiled using cDNA microarrays in the sixth day of exposition to EC50 metals. Genes involved in Cu and Cd chronic stress belonging to various functional categories suffered shallow modifications. This possibly indicates that G. tenuistipitata would be in the acclimatization process. In addition, the expression of nine stress genes accompanied by analysis of the photosynthetic rate of seaweed to both metals in three different time frames was analyzed. Genetic variation linked to the mechanism of resistance of the algae, determined from EC50 culture conditions established for two metals, occurred in the early hours of treatment. It was found that G. tenuistipitata was able to accumulate these two metals and to resist and acclimate to the negative effects produced by these elements. The temporal analysis from the nine specific genes showed some specific transcriptional responses of the G. tenuistipitata, exposed to Cu and Cd. Three-condition experiment, control cells cultivated in seawater enriched with von Stosch solution vs. copper and cadmium (indepedent) treated cells. Biological replicates: 4 control, 2 copper treated, 2 cadmium treated. All independently grown and harvested. Four replicates per array.
2013-06-01 | E-GEOD-42988 | biostudies-arrayexpress
Project description:The precise pathogenic mechanism in Cu exposure-cause nephrotoxicity remains unclear. This study investigated the underlying molecular mechanism of copper sulfate (CuSO4)-induced nephrotoxicity. Mice were treated with CuSO4 at 50, 100, 200 mg/kg/day or co-treated with CuSO4 (200 mg/kg/day) and 4-phenylbutyric acid (4-PBA, 100 mg/kg/day) for 28 consecutive days. HEK293 cells were treated with CuSO4 (400 ?M) with or without superoxide dismutase, catalase or 4-PBA for 24 h. Results showed that CuSO4 exposure can cause renal dysfunction and tubular necrosis in the kidney tissues of mice. CuSO4 exposure up-regulated the activities and mRNA expression of caspases-9 and -3 as well as the expression of glucose-regulated protein 78 (GRP78), GRP94, DNA damage-inducible gene 153 (GADD153/CHOP), caspase-12 mRNAs in the kidney tissues. Furthermore, superoxide dismutase and catalase pre-treatments partly inhibited CuSO4-induced cytotoxicity by decreasing reactive oxygen species (ROS) production, activities of caspases-9 and -3 and DNA fragmentations in HEK293 cells. 4-PBA co-treatment significantly improved CuSO4-induced cytotoxicity in HEK293 cells and inhibited CuSO4 exposure-induced renal dysfunction and pathology damage in the kidney tissues. In conclusion, our results reveal that oxidative stress and endoplasmic reticulum stress contribute to CuSO4-induced nephrotoxicity. Our study highlights that targeting endoplasmic reticulum and oxidative stress may offer an approach for Cu overload-caused nephrotoxicity.
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Project description:In eukaryotic cells, the spatial regulation of protein expression is frequently conferred through the coupling of mRNA localization and the local control of translation. mRNA localization to the endoplasmic reticulum (ER) is a prominent example of such regulation and serves a ubiquitous role in segregating the synthesis of secretory and integral membrane proteins to the ER. Recent genomic and biochemical studies have now expanded this view to suggest a role for the ER in global protein synthesis. We have utilized cell fractionation and ribosome profiling to obtain a genomic survey of the subcellular organization of mRNA translation and report that ribosomal loading of mRNAs, a proxy for mRNA translation, is biased to the ER. Notably, ER-associated mRNAs encoding both cytosolic and topogenic signal-encoding proteins display similar ribosome loading densities, suggesting that ER-associated ribosomes serve a global role in mRNA translation. We propose that the partitioning of mRNAs and their translation between the cytosol and ER compartments may represent a novel mechanism for the post-transcriptional regulation of gene expression. HEK293 cells were fractionated between the cytosol and endoplasmic reticulum. Within each fraction, ribosome footprints were generated and sequenced. In parallel, total mRNA was sequenced.
2011-12-20 | E-GEOD-31539 | biostudies-arrayexpress
Project description:The study of macroalgae capacity to acclimate and recover in environments contaminated with Cu and Cd could prove a promising way to understand the tolerance mechanisms of these seaweeds against different pollutants. This study used as a model organism Gracilaria tenuistipitata (Rhodophyta), a macroalga with economic and ecological importance. The partial transcriptome of G. tenuistipitata was profiled using cDNA microarrays in the sixth day of exposition to EC50 metals. Genes involved in Cu and Cd chronic stress belonging to various functional categories suffered shallow modifications. This possibly indicates that G. tenuistipitata would be in the acclimatization process. In addition, the expression of nine stress genes accompanied by analysis of the photosynthetic rate of seaweed to both metals in three different time frames was analyzed. Genetic variation linked to the mechanism of resistance of the algae, determined from EC50 culture conditions established for two metals, occurred in the early hours of treatment. It was found that G. tenuistipitata was able to accumulate these two metals and to resist and acclimate to the negative effects produced by these elements. The temporal analysis from the nine specific genes showed some specific transcriptional responses of the G. tenuistipitata, exposed to Cu and Cd.
2013-06-01 | GSE42988 | GEO
Project description:Immunogenic cell death (ICD) offers a method of stimulating the immune system to attack and remove cancer cells. We report a copper(II) complex containing a Schiff base ligand and a polypyridyl ligand, 4, capable of inducing ICD in breast cancer stem cells (CSCs). Complex 4 kills both bulk breast cancer cells and breast CSCs at sub-micromolar concentrations. Notably, 4 exhibits greater potency (one order of magnitude) towards breast CSCs than salinomycin (an established breast CSC-potent agent) and cisplatin (a clinically approved anticancer drug). Epithelial spheroid studies show that 4 is able to selectively inhibit breast CSC-enriched HMLER-shEcad spheroid formation and viability over non-tumorigenic breast MCF10 A spheroids. Mechanistic studies show that 4 operates as a Type II ICD inducer. Specifically, 4 readily enters the endoplasmic reticulum (ER) of breast CSCs, elevates intracellular reactive oxygen species (ROS) levels, induces ER stress, evokes damage-associated molecular patterns (DAMPs), and promotes breast CSC phagocytosis by macrophages. As far as we are aware, 4 is the first metal complex to induce ICD in breast CSCs and promote their engulfment by immune cells.
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Project description:The copper(II) complex A0 induces a type of non-apoptotic cell death also known as paraptosis. Paraptosis involves extensive endoplasmic reticulum vacuolization in the absence of caspase activation. A wide panel of human cancer cell lines was used to demonstrate differences in cytotoxicity by the paraptosis-inducing drug A0 and the metal-based pro-apoptotic drug cisplatin. Gene expression profiling of the human fibrosarcoma HT1080 cells showed that, while cisplatin induced p53 targets, A0 up-regulated genes involved in the unfolded protein response (UPR) and response to heavy metals. The cytotoxic effects of A0 were associated with inhibition of the ubiquitin-proteasome system and accumulation of ubiquitinylated proteins, in a manner dependent on protein synthesis. Cycloheximide inhibited the accumulation of ubiquitinylated proteins and hampered A0-induced cell death process. The occurrence of the UPR during A0-induced death process was shown by the increased abundance of spliced XBP1 mRNA, transient eIF2alpha phosphorylation, and a series of downstream events, including attenuation of global protein synthesis and increased expression of ATF4, CHOP, BIP, and GADD34. Mouse embryonic fibroblasts expressing a mutant eIF2alpha, which could not be phosphorylated, were more resistant to A0 than wild type cells, pointing to a pro-death role of eIF2alpha phosphorylation. A0 may thus represent the prototypical member of a new class of compounds that cause paraptotic cell death via mechanisms involving eIF2alpha phosphorylation and the UPR.
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