Iron loading induces cholesterol synthesis and sensitizes endothelial cells to TNFα-mediated apoptosis

Fisher, Allison L.; Srole, Daniel N.; Palaskas, Nicolaos; Meriwether, David; Reddy, Srinivasa T.; Ganz, Tomas; Nemeth, Elizabeta

doi:10.1016/j.jbc.2021.101156

Cited by 15 publications

(11 citation statements)

References 64 publications

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“…These data suggest that ROS might contribute to the induction of Chol synthesis, likely by inducing HMGCR expression (rate-limiting enzyme of the de novo pathway) ( Figure 6 ), as it was previously shown. 39 , 68 ROS are also able to increase HMGCR activity by inducing protein phosphatase 2A (PP2A) dephosphorylation activity by p38. 69 Surprisingly, the increased Chol synthesis after Cu treatment is even higher than after Fe and TBH treatments, although no differences in ROS generation were observed.…”

Section: Resultsmentioning

confidence: 99%

Effect of Sublethal Copper Overload on Cholesterol De Novo Synthesis in Undifferentiated Neuronal Cells

et al. 2022

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Although copper (Cu) is an essential trace metal for cells, it can induce harmful effects as it participates in the Fenton reaction. Involuntary exposure to Cu overload is much more common than expected and has been linked with neurodegeneration, particularly with Alzheimer’s disease (AD) evidenced by a positive correlation between free Cu in plasma and the severity of the disease. It has been suggested that Cu imbalance alters cholesterol (Chol) homeostasis and that high membrane Chol promotes the amyloidogenic processing of the amyloid precursor protein (APP) secreting the β-amyloid (Aβ) peptide. Despite the wide knowledge on the effects of Cu in mature brain metabolism, the consequence of its overload on immature neurons remains unknown. Therefore, we used an undifferentiated human neuroblastoma cell line (SH-SY5Y) to analyze the effect of sublethal concentrations of Cu on 1— de novo Chol synthesis and membrane distribution; 2—APP levels in cells and its distribution in membrane rafts; 3—the levels of Aβ in the culture medium. Our results demonstrated that Cu increases reactive oxygen species (ROS) and favors Chol de novo synthesis in both ROS-dependent and independent manners. Also, at least part of these effects was due to the activation of 3-hydroxy-3-methyl glutaryl CoA reductase (HMGCR). In addition, Cu increases the Chol/PL ratio in the cellular membranes, specifically Chol content in membrane rafts. We found no changes in total APP cell levels; however, its presence in membrane rafts increases with the consequent increase of Aβ in the culture medium. We conclude that Cu overload favors Chol de novo synthesis in both ROS-dependent and independent manners, being at least in part, responsible for the high Chol levels found in the cell membrane and membrane rafts. These may promote the redistribution of APP into the rafts, favoring the amyloidogenic processing of this protein and increasing the levels of Aβ.

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Section: Resultsmentioning

confidence: 99%

Effect of Sublethal Copper Overload on Cholesterol De Novo Synthesis in Undifferentiated Neuronal Cells

et al. 2022

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“…Cells were treated with ferric ammonium citrate (FAC), a commonly used form of iron [ 36 ]. Cells were then incubated with 5 μM Mito-FerroGreen and/or 5 μM MitoSOX in HBSS for the detection of Fe 2+ and mtROS, respectively.…”

Section: Methodsmentioning

confidence: 99%

Integrated regulation of stress responses, autophagy and survival by altered intracellular iron stores

Wang

Liu

et al. 2022

Redox Biology

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“…Cell apoptosis was detected using an Annexin V (FITC)/PI Apoptosis Detection Kit. 28 Briefly, 786-O cells were treated with the indicated concentrations of [Ru(tpy-CM) 2 ]Cl 2 ( 4a ), then washed three times with PBS. After dissociation, the cells were resuspended in PBS and the PBS was removed by centrifugation.…”

Section: Methodsmentioning

confidence: 99%

Synthesis of a novel nitrogen mustard–conjugated bis-terpyridine ruthenium(II) complex as a potent anticancer agent that induces cell cycle arrest and apoptosis

Liang

Huang

Wang

et al. 2022

Journal of Chemical Research

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A fairly small-sized aryl nitrogen mustard–conjugated terpyridine is synthesized in only two steps as a ligand to chelate with RuCl3 to afford a [Ru(tpy-CM)2]Cl2 complex. This complex exhibits prominent antiproliferative activity toward several tumor cells. Further studies conclusively show that the complex suppresses human renal clear cell carcinoma cells (786-O cells) by inducing G1 phase cell cycle arrest and apoptosis. This work provides a synthetic and therapeutic model for nitrogen mustard-containing metal complexes.

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Iron loading induces cholesterol synthesis and sensitizes endothelial cells to TNFα-mediated apoptosis

Abstract: Iron loading induces cholesterol synthesis and sensitizes endothelial cells to TNFα-mediated apoptosis,

Cited by 15 publications

References 64 publications

Effect of Sublethal Copper Overload on Cholesterol De Novo Synthesis in Undifferentiated Neuronal Cells

Effect of Sublethal Copper Overload on Cholesterol De Novo Synthesis in Undifferentiated Neuronal Cells

Integrated regulation of stress responses, autophagy and survival by altered intracellular iron stores

Synthesis of a novel nitrogen mustard–conjugated bis-terpyridine ruthenium(II) complex as a potent anticancer agent that induces cell cycle arrest and apoptosis

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