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

Lucas, Luisa; Hernández-Alcoceba, Rubén; Penalva, Verónica; Lacal, Juan Carlos

doi:10.1038/sj.onc.1204216

Cited by 42 publications

(31 citation statements)

References 42 publications

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“…This result coincides with the observations of Berkovic et al for a leukemic cell line (1). In contrast, it differs from those reported for other tumor cells, where HePC induced PLD stimulation (36) or modulation in the amount of PLD according to the HePC exposure frequency (16). However, our result concerning PLD should be considered preliminary, and a more extensive enzymology investigation of PLD in L. donovani must be run to draw conclusions about the effect of HePC on PLD activity.…”

Section: (34)contrasting

confidence: 50%

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Miltefosine Affects Lipid Metabolism in Leishmania donovani Promastigotes

Rakotomanga

Blanc

Gaudin

et al. 2007

Antimicrob Agents Chemother

150

120

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Miltefosine (hexadecylphosphocholine [ HePC]) is the first orally active antileishmanial drug. Transient HePC treatment of Leishmania donovani promastigotes at 10 M significantly reduced the phosphatidylcholine content and enhanced the phosphatidylethanolamine (PE) content in parasite membranes, suggesting a partial inactivation of PE-N-methyltransferase. Phospholipase D activity did not seem to be affected by HePC. In addition, the enhancement of the lysophosphatidylcholine content could be ascribed to phospholipase A2 activation. Moreover, transient HePC treatment had no effect on the fatty acid alkyl chain length or the fatty acid unsaturation rate. Concerning sterols, we found a strong reduction of the C 24 alkylated sterol content, and the enhancement of the cholesterol content could be the result of the HePC condensation effect with sterols.

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Section: (34)contrasting

confidence: 50%

“…HePC could be a PLD pseudosubstrate because of its chemical structure. Moreover, a PLD stimulation was described in tumoral cells by Wieder et al (36) and Lucas et al (16) after HePC treatment.…”

Section: Resultsmentioning

confidence: 99%

Miltefosine Affects Lipid Metabolism in Leishmania donovani Promastigotes

Rakotomanga

Blanc

Gaudin

et al. 2007

Antimicrob Agents Chemother

150

120

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“…How alkylphospholipids activate the MEK/ERK pathway is still unknown. In some in vitro models, ALKs modulate several signal transduction pathways, including protein kinase C, phospholipase C, and phospholipase D (67,68). It is quite possible that modulation of these and other unknown pathways by ALKs may promote the activation of MAPKs.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Activation of p21waf1/cip1 by Alkylphospholipids

et al. 2004

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Alkylphospholipids (ALKs) are a novel class of antitumor agents with an unknown mechanism of action. The first ALK tested in the clinic, miltefosine, has been approved recently in Europe for the local treatment of patients with cutaneous metastasis. Perifosine, the only available oral ALK, is being studied currently in human cancer clinical trials. We have shown previously that perifosine induces p21 waf1/cip1 in a p53-independent fashion and that induction of p21 waf1/cip1 is required for the perifosineinduced cell cycle arrest because cell lines lacking p21 waf1/cip1 are refractory to perifosine. In this report, we investigated the mechanism by which perifosine induces p21 waf1/cip1 protein expression. We observed that perifosine induces the accumulation of p21 waf1/cip1 mRNA without affecting p21 waf1/cip1 mRNA stability. Using several p21 waf1/cip1 promoter-driven luciferase reporter plasmids, we observed that perifosine activates the 2.4-kb full-length p21 waf1/cip1 promoter as well as a p21 promoter construct lacking p53-binding sites, suggesting that perifosine activates the p21 waf1/cip1 promoter independent of p53. The minimal p21 promoter region required for perifosine-induced p21 promoter activation contains four consensus Sp1-binding sites. Mutations in each particular Sp1 site block perifosine-induced p21 waf1/cip1 expression. Moreover, we showed that perifosine activates the mitogen-activated protein/extracellular signal-regulated kinase pathway, and this activation promotes the phosphorylation of Sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased Sp1 binding and enhanced p21 waf1/cip1 transcription. These results represent a novel mechanism by which alkylphospholipids modulate transcription, and may contribute to the discovery of new signal transduction pathways crucial for normal and neoplastic cell cycle control.

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“…However, a clear mechanism of action has not been established yet. An important mechanism for HePC-induced biological effects may be the inhibition of phospholipase C [8], phospholipase A 2 [9] or the activation of phospholipase D [10,11] which may be achieved by protein kinase C (PKC) dependent or independent mechanism, depending of the cell line investigated [11]. The toxicity of HePC may also be related to a disruption of calcium homeostasis [12].…”

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confidence: 99%