scholarly journals Targeting Scavenger Receptor Type B1 In Cholesterol-Addicted Lymphomas Abolishes Glutathione Peroxidase 4 and Results in Ferroptosis

2020 ◽  
Author(s):  
Jonathan S. Rink ◽  
Adam Yuh Lin ◽  
Kaylin M. McMahon ◽  
Andrea E. Calvert ◽  
Shuo Yang ◽  
...  
Keyword(s):  
Cell Death ◽  
Glutathione Peroxidase ◽  
Cholesterol Synthesis ◽  
De Novo ◽  
Metabolic Response ◽  
Membrane Lipids ◽  
Scavenger Receptor ◽  
Receptor Type ◽  
Lymphoma Cells ◽  
Cholesterol Uptake

ABSTRACTNormal human cells can either synthesize or uptake cholesterol from lipoproteins to meet their metabolic requirements. Some malignant cells absolutely require cholesterol uptake from lipoproteins for survival because de novo cholesterol synthesis genes are transcriptionally silent or mutated. Recent data suggest that lymphoma cells dependent upon lipoprotein-mediated cholesterol uptake are also dependent on the expression of the lipid hydroperoxidase enzyme glutathione peroxidase 4 (GPX4) to prevent cell death by ferroptosis. Ferroptosis is an oxygen-and iron-dependent cell death mechanism that results from the accumulation of oxidized lipids in cell membranes. To study mechanisms linking cholesterol uptake with ferroptosis, we employed lymphoma cell lines known to be sensitive to cholesterol uptake depletion and treated them with high-density lipoprotein-like (HDL) nanoparticles (HDL NPs). HDL NPs are a cholesterol-poor ligand of the receptor for cholesterol-rich HDL, scavenger receptor type B-1 (SCARB1). Our data reveal that HDL NP treatment activates a compensatory metabolic response in treated cells favoring de novo cholesterol synthesis, which is accompanied by reduced expression of GPX4. As a result, accumulation of oxidized membrane lipids leads to cell death through a mechanism consistent with ferroptosis. Furthermore, ferroptosis was validated in vivo after systemic administration of HDL NPs in mouse lymphoma xenografts and in primary samples obtained from patients with lymphoma. In summary, targeting SCARB1 with HDL NPs in cholesterol uptake addicted lymphoma cells abolishes GPX4 and cancer cell death ensues through a mechanism consistent with ferroptosis.

scholarly journals Targeted reduction of cholesterol uptake in cholesterol-addicted lymphoma cells blocks turnover of oxidized lipids to cause ferroptosis

2020 ◽  
pp. jbc.RA120.014888
Author(s):  
Jonathan S. Rink ◽  
Adam Lin ◽  
Kaylin M. McMahon ◽  
Andrea E Calvert ◽  
Shuo Yang ◽  
...  
Keyword(s):  
Cell Death ◽  
Cholesterol Synthesis ◽  
De Novo ◽  
Metabolic Response ◽  
Membrane Lipids ◽  
Oxidized Lipids ◽  
Lymphoma Cells ◽  
Cholesterol Uptake ◽  
Lipid Species

Normal human cells can either synthesize cholesterol or take it up from lipoproteins to meet their metabolic requirements. In some malignant cells, de novo cholesterol synthesis genes are transcriptionally silent or mutated, meaning that cholesterol uptake from lipoproteins is required for survival. Recent data suggest that lymphoma cells dependent upon lipoprotein-mediated cholesterol uptake are also subject to ferroptosis, an oxygen- and iron-dependent cell death mechanism triggered by accumulation of oxidized lipids in cell membranes unless the lipid hydroperoxidase, glutathione peroxidase 4 (GPX4), reduces these toxic lipid species. To study mechanisms linking cholesterol uptake with ferroptosis and determine the potential role of the high-density lipoprotein (HDL) receptor as a target for cholesterol depleting therapy, we treated lymphoma cell lines known to be sensitive to reduction of cholesterol uptake with HDL-like nanoparticles (HDL NPs). HDL NPs are a cholesterol-poor ligand that binds to the receptor for cholesterol-rich HDL, scavenger receptor type B-1 (SCARB1). Our data reveal that HDL NP treatment activates a compensatory metabolic response in treated cells towards increased de novo cholesterol synthesis, which is accompanied by nearly complete reduction in expression of GPX4. As a result, oxidized membrane lipids accumulate leading to cell death through a mechanism consistent with ferroptosis. We obtained similar results in vivo after systemic administration of HDL NPs in mouse lymphoma xenografts and in primary samples obtained from patients with lymphoma. In summary, targeting SCARB1 with HDL NPs in cholesterol uptake-addicted lymphoma cells abolishes GPX4 resulting in cancer cell death by a mechanism consistent with ferroptosis.

scholarly journals Inhibition of polo-like kinase 1 (PLK1) facilitates reactivation of gamma-herpesviruses and their elimination

2021 ◽  
Vol 17 (7) ◽  
pp. e1009764
Author(s):  
Ayan Biswas ◽  
Dawei Zhou ◽  
Guillaume N. Fiches ◽  
Zhenyu Wu ◽  
Xuefeng Liu ◽  
...  
Keyword(s):  
Cell Death ◽  
De Novo ◽  
People Living With Hiv ◽  
Lymphoma Cells ◽  
Barr Virus ◽  
Cytopathic Effects ◽  
Lytic Reactivation ◽  
Latently Infected ◽  
Epstein Barr ◽  
Living With Hiv

Both Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) establish the persistent, life-long infection primarily at the latent status, and associate with certain types of tumors, such as B cell lymphomas, especially in immuno-compromised individuals including people living with HIV (PLWH). Lytic reactivation of these viruses can be employed to kill tumor cells harboring latently infected viral episomes through the viral cytopathic effects and the subsequent antiviral immune responses. In this study, we identified that polo-like kinase 1 (PLK1) is induced by KSHV de novo infection as well as lytic switch from KSHV latency. We further demonstrated that PLK1 depletion or inhibition facilitates KSHV reactivation and promotes cell death of KSHV-infected lymphoma cells. Mechanistically, PLK1 regulates Myc that is critical to both maintenance of KSHV latency and support of cell survival, and preferentially affects the level of H3K27me3 inactive mark both globally and at certain loci of KSHV viral episomes. Furthremore, we recognized that PLK1 inhibition synergizes with STAT3 inhibition to efficiently induce KSHV reactivation. We also confirmed that PLK1 depletion or inhibition yields the similar effect on EBV lytic reactivation and cell death of EBV-infected lymphoma cells. Lastly, we noticed that PLK1 in B cells is elevated in the context of HIV infection and caused by HIV Nef protein to favor KSHV/EBV latency.

scholarly journals Ferroptosis induces membrane blebbing in placental trophoblasts

2021 ◽  
pp. jcs.255737
Author(s):  
Kazuhiro Kajiwara ◽  
Ofer Beharier ◽  
Choon-Peng Chng ◽  
Julie P. Goff ◽  
Yingshi Ouyang ◽  
...  
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Molecular Modeling ◽  
Cell Membrane ◽  
Glutathione Peroxidase ◽  
Oxidative Damage ◽  
Membrane Lipids ◽  
Target Cells ◽  
Cytoplasmic Organelle ◽  
Membrane Blebbing

Ferroptosis is a regulated, non-apoptotic form of cell death, characterized by hydroxy-peroxidation of discrete phospholipid hydroperoxides, particularly hydroperoxyl (Hp)- forms of arachidonoyl- and adrenoyl-phosphatidylethanolamine, with a downstream cascade of oxidative damage to membrane lipids, proteins, and DNA, culminating in cell death. We recently showed that human trophoblasts are particularly sensitive to ferroptosis, caused by depletion or inhibition of glutathione peroxidase 4 (GPX4) or the lipase PLA2G6. Here, we show that trophoblastic ferroptosis is accompanied by a dramatic change in trophoblast plasma membrane, with macro-blebbing and vesiculation. Immunofluorescence revealed that ferroptotic cell-derived blebs stained positive for F-actin, but negative for cytoplasmic organelle markers. Transfer of conditioned medium that contained detached macrovesicles or co-culture with blebbing cells did not stimulate ferroptosis in target cells. Molecular modeling showed that the presence of Hp- phosphatidylethanolamine in the cell membrane promoted its stretchability. Together, our data establish that membrane macro-blebbing is characteristic of trophoblast ferroptosis and can serve as a useful marker of this process. Whether or not these blebs are physiologically functional remains to be established.

scholarly journals Angptl4 Upregulates Cholesterol Synthesis in Liver via Inhibition of LPL- and HL-Dependent Hepatic Cholesterol Uptake

2007 ◽  
Vol 27 (11) ◽  
pp. 2420-2427 ◽  
Author(s):  
Laeticia Lichtenstein ◽  
Jimmy F.P. Berbée ◽  
Susan J. van Dijk ◽  
Ko Willems van Dijk ◽  
André Bensadoun ◽  
...  
Keyword(s):  
Cholesterol Synthesis ◽  
Hepatic Cholesterol ◽  
Cholesterol Uptake

scholarly journals RAD50 and RAD51 Define Two Pathways That Collaborate to Maintain Telomeres in the Absence of Telomerase

Genetics ◽  
1999 ◽  
Vol 152 (1) ◽  
pp. 143-152 ◽  
Author(s):  
Siyuan Le ◽  
J Kent Moore ◽  
James E Haber ◽  
Carol W Greider
Keyword(s):  
Cell Death ◽  
Telomere Length ◽  
Gene Conversion ◽  
De Novo ◽  
Dna Recombination ◽  
Telomere Maintenance ◽  
Triple Mutant ◽  
Yeast Telomerase ◽  
Telomere Lengthening

Abstract Telomere length is maintained by the de novo addition of telomere repeats by telomerase, yet recombination can elongate telomeres in the absence of telomerase. When the yeast telomerase RNA component, TLC1, is deleted, telomeres shorten and most cells die. However, gene conversion mediated by the RAD52 pathway allows telomere lengthening in rare survivor cells. To further investigate the role of recombination in telomere maintenance, we assayed telomere length and the ability to generate survivors in several isogenic DNA recombination mutants, including rad50, rad51, rad52, rad54, rad57, xrs2, and mre11. The rad51, rad52, rad54, and rad57 mutations increased the rate of cell death in the absence of TLC1. In contrast, although the rad50, xrs2, and mre11 strains initially had short telomeres, double mutants with tlc1 did not affect the rate of cell death, and survivors were generated at later times than tlc1 alone. While none of the double mutants of recombination genes and tlc1 (except rad52 tlc1) blocked the ability to generate survivors, a rad50 rad51 tlc1 triple mutant did not allow the generation of survivors. Thus RAD50 and RAD51 define two separate pathways that collaborate to allow cells to survive in the absence of telomerase.

scholarly journals The adaptor protein GIPC1 stabilizes the scavenger receptor SR-B1 and increases its cholesterol uptake

2021 ◽  
pp. 100616
Author(s):  
Ziyu Zhang ◽  
Qian Zhou ◽  
Rui Liu ◽  
Li Liu ◽  
Wen-Jun Shen ◽  
...  
Keyword(s):  
Scavenger Receptor ◽  
Adaptor Protein ◽  
Cholesterol Uptake

scholarly journals Cellular pyrimidine imbalance triggers mitochondrial DNA–dependent innate immunity

2021 ◽  
Author(s):  
Hans-Georg Sprenger ◽  
Thomas MacVicar ◽  
Amir Bahat ◽  
Kai Uwe Fiedler ◽  
Steffen Hermans ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Cultured Cells ◽  
De Novo ◽  
Metabolic Response ◽  
Interferon Response ◽  
Type I ◽  
Nucleotide Synthesis ◽  
Pyrimidine Synthesis ◽  
Pyrimidine Nucleotide ◽  
De Novo Pyrimidine Synthesis

AbstractCytosolic mitochondrial DNA (mtDNA) elicits a type I interferon response, but signals triggering the release of mtDNA from mitochondria remain enigmatic. Here, we show that mtDNA-dependent immune signalling via the cyclic GMP–AMP synthase‒stimulator of interferon genes‒TANK-binding kinase 1 (cGAS–STING–TBK1) pathway is under metabolic control and is induced by cellular pyrimidine deficiency. The mitochondrial protease YME1L preserves pyrimidine pools by supporting de novo nucleotide synthesis and by proteolysis of the pyrimidine nucleotide carrier SLC25A33. Deficiency of YME1L causes inflammation in mouse retinas and in cultured cells. It drives the release of mtDNA and a cGAS–STING–TBK1-dependent inflammatory response, which requires SLC25A33 and is suppressed upon replenishment of cellular pyrimidine pools. Overexpression of SLC25A33 is sufficient to induce immune signalling by mtDNA. Similarly, depletion of cytosolic nucleotides upon inhibition of de novo pyrimidine synthesis triggers mtDNA-dependent immune responses in wild-type cells. Our results thus identify mtDNA release and innate immune signalling as a metabolic response to cellular pyrimidine deficiencies.

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