Membranes: a meeting point for lipids, proteins and therapies

Escribá, Pablo V.; González-Ros, José M.; Goñi, Félix M.; Kinnunen, Paavo K.J.; Vı́gh, László; Sánchez-Magraner, Lissete; Fernández, Asia M.; Busquets, Xavier; Horváth, Ibolya; Barceló‐Coblijn, Gwendolyn

doi:10.1111/j.1582-4934.2008.00281.x

Cited by 353 publications

(301 citation statements)

References 346 publications

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“…This is consistent with the induced expression of Hsp70s in response to the activation of PKC [35]. Moreover, the heat-induced accumulation of PS and the BA-induced enhancement of DAG may play a positive regulatory role in PKC activation and consequently in HS induction, since both PS and DAG are essential cofactors of PKC [64,65], but can be differently affected by the different stressors. 20:4-DAG can be subsequently metabolised by DAG lipase to 20:4-monoacylglycerol (20:4-MAG) [66,67] after which AA can be released through the action of monoacylglycerol lipase or fatty acid amide hydrolase action [68].…”

Section: Membranes Are Key Determinants Of Cellular Stress Adaptationsupporting

confidence: 83%

Membrane fluidity matters: Hyperthermia from the aspects of lipids and membranes

Csoboz

Balogh

Kúsz

et al. 2013

International Journal of Hyperthermia

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Hyperthermia is a promising treatment modality for cancer in combination both with radio-and chemotherapy. In spite of its great therapeutic potential, the underlying molecular mechanisms still remain to be clarified. Due to lipid imbalances and 'membrane defects' most of the tumour cells possess elevated membrane fluidity. However, further increasing membrane fluidity to sensitise to chemo-or radiotherapy could have some other effects. In fact, hyperfluidisation of cell membrane induced by membrane fluidiser initiates a stress response as the heat shock protein response, which may modulate positively or negatively apoptotic cell death. Overviewing some recent findings based on a technology allowing direct imaging of lipid rafts in live cells and lipidomics, novel aspects of the intimate relationship between the 'membrane stress' of tumour cells and the cellular heat shock response will be highlighted. Our findings lend support to both the importance of membrane remodelling and the release of lipid signals initiating stress protein response, which can operate in tandem to control the extent of the ultimate cellular thermosensitivity. Overall, we suggest that the fluidity variable of membranes should be used as an independent factor for predicting the efficacy of combinational cancer therapies.

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Section: Membranes Are Key Determinants Of Cellular Stress Adaptationsupporting

confidence: 83%

Membrane fluidity matters: Hyperthermia from the aspects of lipids and membranes

Csoboz

Balogh

Kúsz

et al. 2013

International Journal of Hyperthermia

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“…Cell-signaling networks commonly use proteins capable of reversible membrane targeting (25,26). Recent systems biological approaches have provided examples of how information encoded in the spatiotemporal activity of such proteins can be integrated by key signaling proteins such as ERK to produce a stimulusdependent cellular response (27)(28)(29).…”

Section: Discussionmentioning

confidence: 99%

G-protein signaling leverages subunit-dependent membrane affinity to differentially control βγ translocation to intracellular membranes

O’Neill¹,

Karunarathne²,

Kalyanaraman³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Activation of G-protein heterotrimers by receptors at the plasma membrane stimulates βγ-complex dissociation from the α-subunit and translocation to internal membranes. This intermembrane movement of lipid-modified proteins is a fundamental but poorly understood feature of cell signaling. The differential translocation of G-protein βγ-subunit types provides a valuable experimental model to examine the movement of signaling proteins between membranes in a living cell. We used live cell imaging, mathematical modeling, and in vitro measurements of lipidated fluorescent peptide dissociation from vesicles to determine the mechanistic basis of the intermembrane movement and identify the interactions responsible for differential translocation kinetics in this family of evolutionarily conserved proteins. We found that the reversible translocation is mediated by the limited affinity of the βγ-subunits for membranes. The differential kinetics of the βγ-subunit types are determined by variations among a set of basic and hydrophobic residues in the γ-subunit types. Gprotein signaling thus leverages the wide variation in membrane dissociation rates among different γ-subunit types to differentially control βγ-translocation kinetics in response to receptor activation. The conservation of primary structures of γ-subunits across mammalian species suggests that there can be evolutionary selection for primary structures that confer specific membrane-binding affinities and consequent rates of intermembrane movement.protein-membrane interaction | spatio-temporal dynamics | G protein-coupled receptors C ompared with the vast biochemical information available for signaling proteins from cell-disruptive techniques, much less is known about their spatiotemporal dynamics in the 3D space of an intact living cell. Many important signaling proteins are posttranslationally modified with lipid groups that facilitate their interactions with membranes. Live cell imaging has so far revealed important roles for constitutive cycles that maintain proper localization of lipidated proteins (1) and for dynamic protein redistribution throughout the cell in response to a signal (2), but the detailed nature of lipid-modified protein movement between membranes is generally not well understood.Heterotrimeric G proteins consist of lipid-modified α-and βγ-subunits (3). They are central transducers of the most important signaling pathways in mammals, yet little is known about their intracellular movement. Inactive heterotrimers consist of a GDP-bound α-subunit in complex with a stable βγ-dimer and localize to the plasma membrane (3). Extracellular signals activate transmembrane G-protein-coupled receptors (GPCRs) that catalyze nucleotide exchange on the G-protein α-subunit (3). The βγ-complex can then dissociate from the active α-subunit and translocate from the plasma membrane to intracellular membranes (4-6). βγ translocation has been observed for many different cell types and receptor types, suggesting that it is a common feature of G-protein signaling (4-...

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“…Such modifications can be used for therapeutic purposes, an approach termed ''membrane-lipid therapy'' (7,24). Indeed, lipid molecules such as edelfosine and mitelfosine are potent antineoplastic drugs that target the membrane (25,26), and they induce apoptosis in cancer cells through mechanisms that alter membrane lipid raft organization (26).…”

Section: Discussionmentioning

confidence: 99%

Pivotal role of dihydrofolate reductase knockdown in the anticancer activity of 2-hydroxyoleic acid

Lladó¹,

Terés

Higuera

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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␣-Hydroxy-9-cis-octadecenoic acid, a synthetic fatty acid that modifies the composition and structure of lipid membranes. 2-Hydroxyoleic acid (HOA) generated interest due to its potent, yet nontoxic, anticancer activity. It induces cell cycle arrest in human lung cancer (A549) cells and apoptosis in human leukemia (Jurkat) cells. These two pathways may explain how HOA induces regression of a variety of cancers. We showed that HOA repressed the expression of dihydrofolate reductase (DHFR), the enzyme responsible for tetrahydrofolate (THF) synthesis. Folinic acid, which readily produces THF without the participation of DHFR, reverses the antitumor effects of HOA in A549 and Jurkat cells, as well as the inhibitory influence on cyclin D and cdk2 in A549 cells, and on DNA and PARP degradation in Jurkat cells. This effect was very specific, because either elaidic acid (an analog of HOA) or other lipids, failed to alter A549 or Jurkat cell growth. THF is a cofactor necessary for DNA synthesis. Thus, impairment of DNA synthesis appears to be a common mechanism involved in the different responses elicited by cancer cells following treatment with HOA, namely cell cycle arrest or apoptosis. Compared with other antifolates, such as methotrexate, HOA did not directly inhibit DHFR but rather, it repressed its expression, a mode of action that offers certain therapeutic advantages. These results not only demonstrate the effect of a fatty acid on the expression of DHFR, but also emphasize the potential of HOA to be used as a wide-spectrum drug against cancer.anticancer ͉ DNA ͉ membrane-lipid therapy ͉ neoplasia ͉ nutrigenetics 2 -Hydroxyoleic acid (HOA) is a potent anticancer drug whose molecular mechanism of action is still not fully understood. Although HOA induces cell cycle exit in human lung cancer (A549) cells (1), it induces apoptosis in human leukemia cells (2). The IC 50 of this drug for most cancer cells studied is in the range of 30-150 M, whereas its IC 50 in normal cells is over 5,000 M (2). Thus, this drug does not produce toxicity at therapeutic doses despite acting efficiently in cell and animal models of human cancers (2, 3). Hence, it is important to define the mode of action of this compound and whether common molecular events underlie its therapeutic effects and the regression of different types of cancer.HOA was developed on the basis that the lipid composition and structure of the plasma membrane can be altered by certain antitumor drugs and that these modifications are involved in their action against cancer (4, 5). In this context, anthracyclines that are unable to enter cancer cells or bind to DNA still have strong antitumor activity (6). Indeed, those used in human therapy regulate plasma membrane structure, and they induce changes in the localization and activity of important peripheral signaling proteins, such as G proteins and PKC (4,7,8). This mode of action also appears to be responsible for the activity of hexamethylene bisacetamide against cancers (9, 10).In the search for molecules capable of i...

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Membranes: a meeting point for lipids, proteins and therapies

Cited by 353 publications

References 346 publications

Membrane fluidity matters: Hyperthermia from the aspects of lipids and membranes

Membrane fluidity matters: Hyperthermia from the aspects of lipids and membranes

G-protein signaling leverages subunit-dependent membrane affinity to differentially control βγ translocation to intracellular membranes

Pivotal role of dihydrofolate reductase knockdown in the anticancer activity of 2-hydroxyoleic acid

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