Intracellular cholesterol level regulates sensitivity of glioblastoma cells against temozolomide-induced cell death by modulation of caspase-8 activation via death receptor 5-accumulation and activation in the plasma membrane lipid raft

One of the most relevant drawbacks in medicine is the ability of drugs and/or imaging agents to reach cells. Nanotechnology opened new horizons in drug delivery, and silver nanoparticles (AgNPs) represent a promising delivery vehicle for their adjustable size and shape, high-density surface ligand attachment, etc. AgNPs cellular uptake involves different endocytosis mechanisms, including lipid raft-mediated endocytosis. Since static magnetic fields (SMFs) exposure induces plasma membrane perturbation, including the rearrangement of lipid rafts, we investigated whether SMF could increase the amount of AgNPs able to pass the peripheral blood lymphocytes (PBLs) plasma membrane. To this purpose, the effect of 6-mT SMF exposure on the redistribution of two main lipid raft components (i.e., disialoganglioside GD3, cholesterol) and on AgNPs uptake efficiency was investigated. Results showed that 6 mT SMF: (i) induces a time-dependent GD3 and cholesterol redistribution in plasma membrane lipid rafts and modulates gene expression of ATP-binding cassette transporter A1 (ABCA1), (ii) increases reactive oxygen species (ROS) production and lipid peroxidation, (iii) does not induce cell death and (iv) induces lipid rafts rearrangement, that, in turn, favors the uptake of AgNPs. Thus, it derives that SMF exposure could be exploited to enhance the internalization of NPs-loaded therapeutic or diagnostic molecules.

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Membrane lipid rafts are disturbed in the response of rat skeletal muscle to short-term disuse

AJP Cell Physiology ◽

10.1152/ajpcell.00365.2016 ◽

2017 ◽

Vol 312 (5) ◽

pp. C627-C637 ◽

Cited By ~ 19

Author(s):

Alexey M. Petrov ◽

Violetta V. Kravtsova ◽

Vladimir V. Matchkov ◽

Alexander N. Vasiliev ◽

Andrey L. Zefirov ◽

...

Keyword(s):

Skeletal Muscle ◽

Plasma Membrane ◽

Lipid Rafts ◽

Lipid Raft ◽

Motor Nerve ◽

Membrane Lipid ◽

Hindlimb Suspension ◽

Cholera Toxin B Subunit ◽

Plasma Membrane Lipid ◽

Intracellular Ca

Marked loss of skeletal muscle mass occurs under various conditions of disuse, but the molecular and cellular mechanisms leading to atrophy are not completely understood. We investigate early molecular events that might play a role in skeletal muscle remodeling during mechanical unloading (disuse). The effects of acute (6–12 h) hindlimb suspension on the soleus muscles from adult rats were examined. The integrity of plasma membrane lipid rafts was tested utilizing cholera toxin B subunit or fluorescent sterols. In addition, resting intracellular Ca2+ level was analyzed. Acute disuse disturbed the plasma membrane lipid-ordered phase throughout the sarcolemma and was more pronounced in junctional membrane regions. Ouabain (1 µM), which specifically inhibits the Na-K-ATPase α2 isozyme in rodent skeletal muscles, produced similar lipid raft changes in control muscles but was ineffective in suspended muscles, which showed an initial loss of α2 Na-K-ATPase activity. Lipid rafts were able to recover with cholesterol supplementation, suggesting that disturbance results from cholesterol loss. Repetitive nerve stimulation also restores lipid rafts, specifically in the junctional sarcolemma region. Disuse locally lowered the resting intracellular Ca2+ concentration only near the neuromuscular junction of muscle fibers. Our results provide evidence to suggest that the ordering of lipid rafts strongly depends on motor nerve input and may involve interactions with the α2 Na-K-ATPase. Lipid raft disturbance, accompanied by intracellular Ca2+ dysregulation, is among the earliest remodeling events induced by skeletal muscle disuse.

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FLIP Protects against Hypoxia/Reoxygenation-Induced Endothelial Cell Apoptosis by Inhibiting Bax Activation

Molecular and Cellular Biology ◽

10.1128/mcb.25.11.4742-4751.2005 ◽

2005 ◽

Vol 25 (11) ◽

pp. 4742-4751 ◽

Cited By ~ 28

Author(s):

Xue Wang ◽

Yong Wang ◽

Jinglan Zhang ◽

Hong Pyo Kim ◽

Stefan W. Ryter ◽

...

Keyword(s):

Endothelial Cells ◽

Cell Death ◽

Plasma Membrane ◽

Golgi Apparatus ◽

Death Receptor ◽

Mouse Lung ◽

Caspase 8 ◽

Apoptotic Pathways ◽

Disc Formation ◽

Hypoxia Reoxygenation

ABSTRACT Hypoxia/reoxygenation causes cell death, yet the underlying regulatory mechanisms remain partially understood. Recent studies demonstrate that hypoxia/reoxygenation can activate death receptor and mitochondria-dependent apoptotic pathways, involving Bid and Bax mitochondrial translocation and cytochrome c release. Using mouse lung endothelial cells (MLEC), we examined the role of FLIP, an inhibitor of caspase 8, in hypoxia/reoxygenation-induced cell death. FLIP protected MLEC against hypoxia/reoxygenation by blocking both caspase 8/Bid and Bax/mitochondrial apoptotic pathways. FLIP inhibited Bax activation in wild-type and Bid−/− MLEC, indicating independence from the caspase 8/Bid pathway. FLIP also inhibited the expression and activation of protein kinase C (PKC) (α, ζ) during hypoxia/reoxygenation and promoted an association of inactive forms of PKC with Bax. Surprisingly, FLIP expression also inhibited death-inducing signal complex (DISC) formation in the plasma membrane and promoted the accumulation of the DISC in the Golgi apparatus. FLIP expression also upregulated Bcl-XL, an antiapoptotic protein. In conclusion, FLIP decreased DISC formation in the plasma membrane by blocking its translocation from the Golgi apparatus and inhibited Bax activation through a novel PKC-dependent mechanism. The inhibitory effects of FLIP on Bax activation and plasma membrane DISC formation may play significant roles in protecting endothelial cells from the lethal effects of hypoxia/reoxygenation.

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RING1 E3 ligase localizes to plasma membrane lipid rafts to trigger FB1-induced programmed cell death in Arabidopsis

The Plant Journal ◽

10.1111/j.1365-313x.2008.03625.x ◽

2008 ◽

Vol 56 (4) ◽

pp. 550-561 ◽

Cited By ~ 59

Author(s):

Shih-Shun Lin ◽

Raquel Martin ◽

Sebastien Mongrand ◽

Steven Vandenabeele ◽

Kuan-Chun Chen ◽

...

Keyword(s):

Cell Death ◽

Plasma Membrane ◽

Programmed Cell Death ◽

Lipid Rafts ◽

E3 Ligase ◽

Membrane Lipid ◽

Plasma Membrane Lipid

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Targeting cholesterol metabolism in glioblastoma: a new therapeutic approach in cancer therapy

Journal of Investigative Medicine ◽

10.1136/jim-2018-000962 ◽

2019 ◽

Vol 67 (4) ◽

pp. 715-719 ◽

Cited By ~ 12

Author(s):

Leila Pirmoradi ◽

Nayer Seyfizadeh ◽

Saeid Ghavami ◽

Amir A Zeki ◽

Shahla Shojaei

Keyword(s):

De Novo ◽

Mevalonate Pathway ◽

Cholesterol Metabolism ◽

Low Density Lipoprotein ◽

Death Receptor ◽

Density Lipoprotein ◽

Membrane Lipid ◽

Death Receptor 5 ◽

Intracellular Cholesterol ◽

X Receptors

Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor known with a poor survival rate despite current advances in the field of cancer. Additional research into the pathophysiology of GBM is urgently needed given the devastating nature of this disease. Recent studies have revealed the unique cellular physiology of GBM cells as compared with healthy astrocytes. Intriguingly, GBM cells are incapable of de novo cholesterol synthesis via the mevalonate pathway. Thus, the survival of GBM cells depends on cholesterol uptake via low-density lipoprotein receptors (LDLRs) in the form of apolipoprotein-E-containing lipoproteins and ATP-binding cassette transporter A1 (ABCA1) that efflux surplus cholesterol out of cells. Liver X receptors regulate intracellular cholesterol levels in neurons and healthy astrocytes through changes in the expression of LDLR and ABCA1 in response to cholesterol and its derivatives. In GBM cells, due to the dysregulation of this surveillance pathway, there is an accumulation of intracellular cholesterol. Furthermore, intracellular cholesterol regulates temozolomide-induced cell death in glioblastoma cells via accumulation and activation of death receptor 5 in plasma membrane lipid rafts. The mevalonate pathway and autophagy flux are also fundamentally related with implications for cell health and death. Thus, via cholesterol metabolism, the mevalonate pathway may be a crucial player in the pathogenesis and treatment of GBM where our current understanding is still lacking. Targeting cholesterol metabolism in GBM may hold promise as a novel adjunctive clinical therapy for this devastating cancer.

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