Accumulation of an alkyl lysophospholipid in tumor cell membranes affects membrane fluidity and tumor cell invasion

Blitterswijk, W. J.

doi:10.1007/bf02537357

Cited by 5 publications

(9 citation statements)

References 7 publications

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“…In recent years, this hypothesis has gained further support. Spontaneous fusion has been reported between normal breast epithelium and breast cancer cells (33)(34)(35)(36), among breast tumor cells themselves (37)(38)(39), between breast cancer epithelium and endothelial cells (40), and between breast cancer epithelium and tumor stromal cells (12,13).…”

Section: Discussionmentioning

confidence: 99%

“…For example, changes in the ratio of cholesterol to phospholipid and in the double-bond index of the associated fatty acids have been shown to alter plasma membrane structure during hypoxic injury (12). In addition, alterations in lipid structure with hypoxia can lead to changes in membrane protein structure and function, resulting in dysregulated enzyme activity and transport properties that could also lead to leakiness of the plasma membrane barrier (13). Unstable cell membranes are biophysically Abbreviations: aMEM, a-minimum essential medium; BAI, brain-specific angiogenesis inhibitor; BiFC, bimolecular fluorescence complementation; CCL, chemokine ligand; CD, cluster of differentiation; CMV, cytomegalovirus; COI, cytochrome c oxidase I; Dock, dedicator of cytokines; EBV, Epstein-Barr virus; ELMO, engulfment cell and mobility protein; GFP, (continued on next page) susceptible to membrane fusion (14,15).…”

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confidence: 99%

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Apoptosis‐induced cancer cell fusion: a mechanism of breast cancer metastasis

et al. 2015

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Although cancer cell fusion has been suggested as a mechanism of cancer metastasis, the underlying mechanisms defining this process are poorly understood. In a recent study, apoptotic cells were newly identified as a type of cue that induces signaling via phosphatidylserine receptors to promote fusion of myoblasts. The microenvironment of breast tumors is often hypoxic, and because apoptosis is greatly increased in hypoxic conditions, we decided to investigate whether the mechanism of breast cancer cell fusion with mesenchymal stem/multipotent stromal cells (MSCs) involves apoptosis. We used a powerful tool for identification and tracking of hybrids based on bimolecular fluorescence complementation (BiFC) and found that breast cancer cells fused spontaneously with MSCs. This fusion was significantly enhanced with hypoxia and signaling associated with apoptotic cells, especially between nonmetastatic breast cancer cells and MSCs. In addition, the hybrids showed a significantly higher migratory capacity than did the parent cells. Taken together, these findings describe a mechanism by which hypoxiainduced apoptosis stimulates fusion between MSCs and breast tumor cells resulting in hybrids with an enhanced migratory capacity that may enable their dissemination to distant sites or metastases. In the long run, this study may provide new strategies for developing novel drugs for preventing cancer metastasis.-Noubissi, F. K., Harkness, T., Alexander, C. M., Ogle, B. M. Apoptosis-induced cancer cell fusion: a mechanism of breast cancer metastasis. FASEB J. 29, 4036-4045 (2015). www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

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Apoptosis‐induced cancer cell fusion: a mechanism of breast cancer metastasis

et al. 2015

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“…Furthermore, Blitterswijk et al [1987al and Heesbeen et al [19911 showed stimulation of PKC by ether-linked lipids. In contrast, other species of PC, such as 1-0-alkyl-2-O-methylglycero-3-phosphocholine, inhibit cell growth [Blitterswijk et al, 1987b;Noseda et al, 19881 in vitro and in vivo. The inhibitory effect of these PCs is likely to be mediated by generation of l-O-alkyl-2-O-methylglycerol, which inhibits DAG-stimulated activity of purified human protein kinase C (PKC) and the binding of phorbol ester to PKC in HL-60 cells [Blitterswijk et al, 1987b;Noseda et al, 19881.…”

Section: Discussionmentioning

confidence: 99%

Naturally occurring ether‐linked phosphatidylcholine activates phosphatidylinositol 3‐kinase and stimulates cell growth

Misra

Ghosh

Varticovski

1994

J of Cellular Biochemistry

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Phosphatidylcholine (PC) from marine invertebrates is enriched in ether-linked forms. PCs from ray fish, Dasyatis sp., and bivalve, Macoma birmanica, used in the present study, contain 65% and 75% (w/w of total PC) of ether-linked forms, respectively. Ether-linked PCs also occur in mammalian membranes. Agonist-mediated hydrolysis of PC generates second messengers which participate in cellular responses. In this study, we tested whether PCs from marine invertebrates directly affect mammalian cell growth and activity of phosphatidylinositol (Pl-3-kinase). Pl-3-kinase participates in mitogenesis initiated by a variety of growth factors. Pl-3-kinase converts polyphosphoinositides to 3' phosphorylated isomers and these products accumulate in response to mitogenic stimuli. Whether cell membrane lipids regulate Pl-3-kinase activity is not known. The marine animal-derived PCs and dioleoyl DAG (dioleoylglycerol) stimulated growth of murine pre-B lymphocytes, whereas chicken PC (egg lecithin) inhibited growth of these cells. Egg lecithin is also a potent inhibitor of Pl-3-kinase activity in vitro. We studied the effect of PCs and DAG on Pl-3-kinase activity. Unlike egg lecithin, marine animal PCs enhanced Pl-3-kinase activity. We investigated the effect of lipids on Pl-3-kinase substrate utilization. PCs enriched in ether-linked species increased utilization of substrates by Pl-3-kinase. PCs purified from marine organisms also contain a substantially higher percentage of the cis-unsaturated fatty acids, especially of the -omega 3 series (25% and 30% of total fatty acids for Dasyatis sp. and Macoma birmanica, respectively), as compared to vertebrate sources. In spite of differences in fatty acid composition, marine PCs and dioleoyl DAG showed similar effects on cell growth and Pl-3-kinase activity. These findings indicate that ether-linked phospholipids activate Pl-3-kinase and may participate in mitogenic responses.

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“…This ether lipid was found to stop tumour cell proliferation by inhibiting cell division, leading to the accumulation of cells in phases G2/M or G0/G1 of the cell cycle (Roos and Berdel, 1986;Engebraaten et al, 1991;Boggs et al, 1995;Lohmeyer and Workman, 1995;Principe and Braquet, 1995;Pushkareva et al, 1999). It also induced Ca 2+independent apoptosis of tumour cells at 10 mM (normal cells are resistant to edelfosine at this concentration) through the activation of Fas/CD95 death receptors (Mollinedo et al, 2004), and has anti-angiogenic (Candal et al, 1994;Vogler et al, 1998) as well as anti-invasive effects (Storme et al, 1985;Van Blitterswijk et al, 1987;Bolscher et al, 1988;Slaton et al, 1994;Haugland et al, 1999;Steelant et al, 2001). Some authors have proposed that the anti-invasive effect of edelfosine could be due to the inhibition of tumour cell migration (Slaton et al, 1994;Haugland et al, 1999), but this remains a highly contentious issue (Storme et al, 1985).…”

Section: Introductionmentioning

confidence: 99%

The SK3/K_Ca2.3 potassium channel is a new cellular target for edelfosine

Potier

Chantôme

Joulin

et al. 2010

British J Pharmacology

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BACKGROUND AND PURPOSE The 1‐O‐octadecyl‐2‐O‐methyl‐sn‐glycero‐3‐phosphocholine (edelfosine) is an ether‐linked phospholipid with promising anti‐cancer properties but some side effects that preclude its full clinical therapeutic exploitation. We hypothesized that this lipid could interact with plasma membrane ion channels and modulate their function. EXPERIMENTAL APPROACH Using cell migration‐proliferation assays, patch clamp, spectrofluorimetry and 125I‐Apamin binding experiments, we studied the effects of edelfosine on the migration of breast cancer MDA‐MB‐435s cells, mediated by the small conductance Ca2+‐activated K+ channel, SK3/KCa2.3. KEY RESULTS Edelfosine (1 µM) caused plasma membrane depolarization by substantially inhibiting activity of SK3/KCa2.3 channels, which we had previously demonstrated to play an important role in cancer cell migration. Edelfosine did not inhibit 125I‐Apamin binding to this SKCa channel; rather, it reduced the calcium sensitivity of SK3/KCa2.3 channel and dramatically decreased intracellular Ca2+ concentration, probably by insertion in the plasma membrane, as suggested by proteinase K experiments. Edelfosine reduced cell migration to the same extent as known SKCa channel blockers. In contrast, K+ channel openers prevented edelfosine‐induced anti‐migratory effects. SK3 protein knockdown decreased cell migration and totally abolished the effect of edelfosine on MDA‐MB‐435s cell migration. In contrast, transient expression of SK3/KCa2.3 protein in a SK3/KCa2.3‐deficient cell line increased cell migration and made these cells responsive to edelfosine. CONCLUSIONS AND IMPLICATIONS Our data clearly establish edelfosine as an inhibitor of cancer cell migration by acting on SK3/KCa2.3 channels and provide insights into the future development of a new class of migration‐targeted, anti‐cancer agents.

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Accumulation of an alkyl lysophospholipid in tumor cell membranes affects membrane fluidity and tumor cell invasion

Cited by 5 publications

References 7 publications

Apoptosis‐induced cancer cell fusion: a mechanism of breast cancer metastasis

Apoptosis‐induced cancer cell fusion: a mechanism of breast cancer metastasis

Naturally occurring ether‐linked phosphatidylcholine activates phosphatidylinositol 3‐kinase and stimulates cell growth

The SK3/K_Ca2.3 potassium channel is a new cellular target for edelfosine

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Accumulation of an alkyl lysophospholipid in tumor cell membranes affects membrane fluidity and tumor cell invasion

Cited by 5 publications

References 7 publications

Apoptosis‐induced cancer cell fusion: a mechanism of breast cancer metastasis

Apoptosis‐induced cancer cell fusion: a mechanism of breast cancer metastasis

Naturally occurring ether‐linked phosphatidylcholine activates phosphatidylinositol 3‐kinase and stimulates cell growth

The SK3/KCa2.3 potassium channel is a new cellular target for edelfosine

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The SK3/K_Ca2.3 potassium channel is a new cellular target for edelfosine