Inhibition of calcium-dependent protein kinase C by hexadecylphosphocholine and 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine do not correlate with inhibition of proliferation of HL60 and K562 cell lines

Berkovic, Dinko; Berkovic, Katharina; Fleer, E. A. M.; Eibl, Hansjörg; Unger, Clemens

doi:10.1016/0959-8049(94)90428-6

Cited by 28 publications

(14 citation statements)

References 18 publications

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“…An assessment of whether these molecules are inhibited under ET18-OCH 3 preincubation conditions that inhibit Raf-1 activation and whether their activation is essential for growth will be required before such a conclusion can be made. There is evidence that inhibition of PKC by ALPs does not correlate with inhibition of cell growth (2,11,12).…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition of protein kinase C (PKC) has been proposed as the mechanism by which ET18-OCH 3 and related compounds inhibit cell proliferation (8), but this is contentious. ET18-OCH 3 may inhibit (9) or activate (10) PKC activity in in vitro assays depending on the mode of presentation of the ALP in the assay, but a number of studies have revealed no correlation between inhibition of cell growth and inhibition of PKC activity (2,11,12). Decreased inositol 1,4,5-trisphosphate (Ins P 3 ) production in response to incubation of cells with antitumor ether lipids has been reported (13) and could be due to inhibition of phosphatidylinositol-specific phospholipase C (PI-PLC) (14).…”

Section: -O -Octadecyl-2-o -Methyl-glycerophosphocholine (Et18-ochmentioning

confidence: 99%

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1-O-octadecyl-2-O-methyl-glycerophosphocholine inhibits the transduction of growth signals via the MAPK cascade in cultured MCF-7 cells.

Zhou¹,

Lü²,

Richard³

et al. 1996

J. Clin. Invest.

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Abstract1-O -Octadecyl-2-O -methyl-glycerophosphocholine (ET18-OCH 3 ) is an ether lipid with selective antiproliferative properties whose mechanism of action is still unresolved. We hypothesized that since ET18-OCH 3 affects a wide variety of cells, its mechanism of action was likely to involve the inhibition of a common widely used pathway for transducing growth signals such as the mitogen-activated protein kinase (MAPK) cascade. To test this, we established conditions whereby quiescent MCF-7 cells took up ET18-OCH 3 in sufficient quantities that inhibited cell proliferation subsequent to the addition of growth medium and examined the activation of components of the MAPK cascade under these conditions. ET18-OCH 3 inhibited the sustained phosphorylation of MAPK resulting in a decrease in the magnitude and duration of activation of MAPK in cells stimulated with serum or EGF. ET18-OCH 3 had no effect on the binding of EGF to its receptors, their activation, or p21 ras activation. However, an interference in the association of Raf-1 with membranes and a resultant decrease in Raf-1 kinase activity in membranes of ET18-OCH 3 -treated cells was observed. ET18-OCH 3 had no direct effect on MAPK or Raf-1 kinase activity. A direct correlation between ET18-OCH 3 accumulation, inhibition of cell proliferation, Raf association with the membrane, and MAPK activation was also established. These results suggest that inhibition of the MAPK cascade by ET18-OCH 3 as a result of its effect on Raf-1 activation may be an important mechanism by which ET18-OCH 3 inhibits cell proliferation. ( J. Clin. Invest. 1996. 98:934-944 .)

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Section: Discussionmentioning

confidence: 99%

Section: -O -Octadecyl-2-o -Methyl-glycerophosphocholine (Et18-ochmentioning

confidence: 99%

1-O-octadecyl-2-O-methyl-glycerophosphocholine inhibits the transduction of growth signals via the MAPK cascade in cultured MCF-7 cells.

Zhou¹,

Lü²,

Richard³

et al. 1996

J. Clin. Invest.

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“…They have been reported to inhibit PKC activity in di erent ways, which could account for their antiproliferative capacity (Seewald et al, 1990;U È berall et al, 1991;Pawelczyk et al, 1993;Berkovic et al, 1994;Maly et al, 1995). Also, HePC can rapidly increase PLD activity in human breast ®broblast cells in a PKC-dependent manner (Wieder et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

“…The ether-linked phospholipid analogues include several families of compounds with antiproliferative, cytotoxic and antitumoral activities whose mechanism of action is poorly understood (Houliham et al, 1995;Storme et al, 1983;Boggs et al, 1995;Geilen et al, 1992;Haase et al, 1991;Wieder et al, 1993;Posse de Chaves et al, 1995;Seewald et al, 1990;U È berall et al, 1991;Pawelczyk et al, 1993;Berkovic et al, 1994;Maly et al, 1995). They have been reported to inhibit PKC activity in di erent ways, which could account for their antiproliferative capacity (Seewald et al, 1990;U È berall et al, 1991;Pawelczyk et al, 1993;Berkovic et al, 1994;Maly et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Modulation of phospholipase D by hexadecylphosphorylcholine: a putative novel mechanism for its antitumoral activity

Lucas¹,

Hernández-Alcoceba

Penalva³

et al. 2001

Oncogene

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“…1-O-Octadecyl-2-O-methyl-rac-glycerophosphocholine, an alkyllysophospholipid analogue, reduced cell proliferation by decreasing serum-or PDGF-activated MAP kinases (24). Both alkyllysophospholipid and hexadecylphosphocholine reduced membrane-associated and cytosolic total PKC activity (25). 1-O-Dodecyl-sn-glycerol, a monoalkylglycerol, reduced membrane-associated total PKC activity, which correlated with cell culture contact inhibition and resulting growth arrest (26).…”

Section: Fig 2 Alkenyl Acylglycerol (Aag) Inhibits Diacylglycerol mentioning

confidence: 99%

Interleukin-1-induced Ether-linked Diglycerides Inhibit Calcium-insensitive Protein Kinase C Isotypes

Mandal¹,

Wang²,

Ernsberger³

et al. 1997

Journal of Biological Chemistry

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It is hypothesized that inflammatory cytokines and vasoactive peptides stimulate distinct species of diglycerides that differentially regulate protein kinase C isotypes. In published data, we demonstrated that interleukin-1, in contrast to endothelin, selectively generates ether-linked diglyceride species (alkyl, acyl-and alkenyl, acylglycerols) in rat mesangial cells, a smooth muscle-like pericyte in the glomerulus. We now demonstrate both in intact cell and in cell-free preparations that these interleukin-1 receptor-generated ether-linked diglycerides inhibit immunoprecipitated protein kinase C ␦ and ⑀ but not activity. Neither interleukin-1 nor endothelin affect de novo protein expression of these protein kinase C isotypes. As down-regulation of calciuminsensitive protein kinase C isotypes has been linked to antimitogenic activity, we investigated growth arrest as a functional correlate for IL-1-generated ether-linked diglycerides. Cell-permeable ether-linked diglycerides mimic the effects of interleukin-1 to induce a growtharrested state in both G-protein-linked receptor-and tyrosine kinase receptor-stimulated mesangial cells. This signaling mechanism implicates cytokine receptorinduced ether-linked diglycerides as second messengers that inhibit the bioactivity of calcium-insensitive protein kinase C isotypes resulting in growth arrest.Interleukin-1 (IL-1) 1 -induced activation of rat glomerular mesangial cells (MC) culminates in an inflammatory phenotype often observed in vivo in models of glomerulosclerosis. Our laboratory has been investigating the early, lipid-mediated signal transduction pathways for inflammatory cytokines in MC with particular emphasis on the distinct molecular species of diglycerides (DG) generated and their regulation of protein kinase C (PKC) activity. We have demonstrated previously that the inflammatory cytokine interleukin-1␣ and the vasoconstrictor peptide, endothelin-1 (ET-1) generate distinct species of DG from different membrane-associated phospholipids in MC (1-3). IL-1 receptor activation selectively generates etherlinked species of DG, namely alkyl, acyl-and alkenyl, acylglycerols, whereas ET-1 receptor activation produces predominantly ester-linked diacylglycerols (1). Our laboratory has also demonstrated previously that these IL-1 generated etherlinked DG, in contrast to the PKC-activating diacylglycerols, inhibit total PKC activity as well as inhibit diacylglycerolstimulated PKC ␣ activation (1). In fact, ether-linked DG may competitively inhibit PKC activation induced by diacylglycerol species (4). Additional studies support this signaling mechanism, as ether-linked DG fail to activate total PKC activity in vitro or only activate PKC in the presence of pharmacological concentrations of calcium (5-8).In light of these findings, our interest has now turned to regulation by ether-linked DG of specific PKC isotypes. The PKC family now includes 12 distinct isotypes subdivided into three categories (9). The calcium-sensitive conventional PKCs consist of alpha (␣), beta (␤ 1 ...

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Inhibition of calcium-dependent protein kinase C by hexadecylphosphocholine and 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine do not correlate with inhibition of proliferation of HL60 and K562 cell lines

Cited by 28 publications

References 18 publications

1-O-octadecyl-2-O-methyl-glycerophosphocholine inhibits the transduction of growth signals via the MAPK cascade in cultured MCF-7 cells.

1-O-octadecyl-2-O-methyl-glycerophosphocholine inhibits the transduction of growth signals via the MAPK cascade in cultured MCF-7 cells.

Modulation of phospholipase D by hexadecylphosphorylcholine: a putative novel mechanism for its antitumoral activity

Interleukin-1-induced Ether-linked Diglycerides Inhibit Calcium-insensitive Protein Kinase C Isotypes

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