Sesquiterpene alcohol cedrol chemosensitizes human cancer cells by destabilizing plasma membrane lipid rafts and inhibits cell proliferation

Chemosensitization of cancer cells with small molecules may improve the therapeutic index of antitumoral agents by making tumor cells sensitive to the drug regimen and thus overcome the treatment resistance and side effects of single therapy. Cell membrane lipid rafts are known to transduce various signaling events in cell proliferation. Sensitizing cancer cells may cause modulation of membrane lipid rafts which may potentially be used in improving anticancer drug response. Cedrol, a natural sesquiterpene alcohol, was used to treat human leukemia K562 and colon cancer HT-29 cell lines, and effects were observed. Cedrol decreased the cell viability by inducing apoptosis in both cell lines by activation of pro-apoptosis protein BID and inhibition of anti-apoptosis proteins Bcl-XL, Bcl-2, and XIAP. Cedrol activated the caspase-9-dependent mitochondrial intrinsic pathway of apoptosis. Furthermore, cedrol inhibited the levels of pAKT, pERK, and pmTOR proteins as well as nuclear and cytoplasmic levels of the p65 subunit of NF-κB. Cedrol caused redistribution of cholesterol and sphingomyelin contents from membrane lipid raft, which was confirmed by a combined additive effect with methyl-β-cyclodextrin (lipid raft-disrupting agent). Lipid raft destabilization by cedrol led to the increased production of ceramides and inhibition of membrane-bound NADPH oxidase 2 enzyme activity. Cholesterol/sphingomyelin-redistributing abilities of cedrol appear as a novel mechanism of growth inhibition of cancer cells. Cedrol can be classified as a natural lipid raft-disrupting agent with possibilities to be used in general studies involving membrane lipid raft modifications.

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Faculty Opinions recommendation of Contamination of nuclear fractions with plasma membrane lipid rafts.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1072051.525027 ◽

2007 ◽

Author(s):

Michael Roth

Keyword(s):

Plasma Membrane ◽

Lipid Rafts ◽

Membrane Lipid ◽

Plasma Membrane Lipid

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1P-0227 Apolipoprotein A-1 interaction with plasma membrane lipid rafts controls cholesterol export from macrophages

Atherosclerosis Supplements ◽

10.1016/s1567-5688(03)90298-4 ◽

2003 ◽

Vol 4 (2) ◽

pp. 69 ◽

Cited By ~ 2

Author(s):

W. Jessup ◽

K. Gaus ◽

L. Kritharides ◽

A. Boettcher ◽

W. Drobnik ◽

...

Keyword(s):

Plasma Membrane ◽

Lipid Rafts ◽

Membrane Lipid ◽

Apolipoprotein A ◽

Plasma Membrane Lipid

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Moderate Static Magnetic Field (6 mT)-Induced Lipid Rafts Rearrangement Increases Silver NPs Uptake in Human Lymphocytes

Molecules ◽

10.3390/molecules25061398 ◽

2020 ◽

Vol 25 (6) ◽

pp. 1398

Author(s):

Cristian Vergallo ◽

Elisa Panzarini ◽

Bernardetta Anna Tenuzzo ◽

Stefania Mariano ◽

Ada Maria Tata ◽

...

Keyword(s):

Plasma Membrane ◽

Lipid Rafts ◽

Lipid Raft ◽

Human Lymphocytes ◽

Peripheral Blood Lymphocytes ◽

Membrane Lipid ◽

Membrane Perturbation ◽

Plasma Membrane Lipid ◽

Silver Nps ◽

Surface Ligand

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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FXR1 regulates transcription and is required for growth of human cancer cells with TP53/FXR2 homozygous deletion

eLife ◽

10.7554/elife.26129 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 6

Author(s):

Yichao Fan ◽

Jiao Yue ◽

Mengtao Xiao ◽

Han Han-Zhang ◽

Yao Vickie Wang ◽

...

Keyword(s):

Cell Proliferation ◽

Cancer Cells ◽

Rna Binding ◽

Cell Transformation ◽

Human Cancer ◽

Homozygous Deletion ◽

Gene Promoters ◽

Neighboring Gene ◽

Human Cancer Cells ◽

Human Cancers

Tumor suppressor p53 prevents cell transformation by inducing apoptosis and other responses. Homozygous TP53 deletion occurs in various types of human cancers for which no therapeutic strategies have yet been reported. TCGA database analysis shows that the TP53 homozygous deletion locus mostly exhibits co-deletion of the neighboring gene FXR2, which belongs to the Fragile X gene family. Here, we demonstrate that inhibition of the remaining family member FXR1 selectively blocks cell proliferation in human cancer cells containing homozygous deletion of both TP53 and FXR2 in a collateral lethality manner. Mechanistically, in addition to its RNA-binding function, FXR1 recruits transcription factor STAT1 or STAT3 to gene promoters at the chromatin interface and regulates transcription thus, at least partially, mediating cell proliferation. Our study anticipates that inhibition of FXR1 is a potential therapeutic approach to targeting human cancers harboring TP53 homozygous deletion.

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DOX-Vit D, a Novel Doxorubicin Delivery Approach, Inhibits Human Osteosarcoma Cell Proliferation by Inducing Apoptosis While Inhibiting Akt and mTOR Signaling Pathways

Pharmaceutics ◽

10.3390/pharmaceutics10030144 ◽

2018 ◽

Vol 10 (3) ◽

pp. 144 ◽

Cited By ~ 7

Author(s):

Zaid Maayah ◽

Ti Zhang ◽

Marcus Forrest ◽

Samaa Alrushaid ◽

Michael Doschak ◽

...

Keyword(s):

Cell Proliferation ◽

Cancer Cells ◽

Signaling Pathways ◽

Human Cancer ◽

Death Receptor ◽

Osteosarcoma Cell ◽

Acquired Drug Resistance ◽

Human Cancer Cells ◽

Mg63 Cells ◽

Delivery Approach

Doxorubicin (DOX) is a very potent and effective anticancer agent. However, the effectiveness of DOX in osteosarcoma is usually limited by the acquired drug resistance. Recently, Vitamin D (Vit-D) was shown to suppress the growth of many human cancer cells. Taken together, we synthesized DOX-Vit D by conjugating Vit-D to DOX in order to increase the delivery of DOX into cancer cells and mitigate the chemoresistance associated with DOX. For this purpose, MG63 cells were treated with 10 µM DOX or DOX-Vit D for 24 h. Thereafter, MTT, real-time PCR and western blot analysis were used to determine cell proliferation, genes and proteins expression, respectively. Our results showed that DOX-Vit D, but not DOX, significantly elicited an apoptotic signal in MG63 cells as evidenced by induction of death receptor, Caspase-3 and BCLxs genes. Mechanistically, the DOX-Vit D-induced apoptogens were credited to the activation of p-JNK and p-p38 signaling pathway and the inhibition of proliferative proteins, p-Akt and p-mTOR. Our findings propose that DOX-Vit D suppressed the growth of MG63 cells by inducing apoptosis while inhibiting cell survival and proliferative signaling pathways. DOX-Vit D may serve as a novel drug delivery approach to potentiate the delivery of DOX into cancer cells.

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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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