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

Oncogene volume 20, pages 1110–1117 (2001)Cite this article

Abstract

Hexadecylphosphorylcholine (HePC, D-18506, INN: Mitelfosine) belongs to the family of alkylphosphocholines with anticancer activity. Previous reports have related its antitumoral activity to their ability to interfere with phospholipid metabolism. However a clear mechanism of action has not been established yet. We have investigated the effect of HePC on two enzymes recently reported to play a role in cell growth proliferation, phospholipase D (PLD) and choline kinase (ChoK). Our results demonstrate that treatment with HePC induces a rapid stimulation of PLD, that may be achieved by PKC dependent or independent mechanisms, depending on the cell line investigated. Both PLD1 and PLD2 isoenzymes are sensitive to HePC activation. By contrast, no effect was observed by HePC on ChoK, a new target for anticancer drug development. Furthermore, in all cell lines tested, a chronic exposure of the cells to HePC abrogates PLD activation by either phorbol esters or HePC itself with no effect on total cellular PLD levels. This is reflected in a strong inhibition of PLD activity. We suggest that the inhibitory effects on PLD by HePC may be related to its antitumoral action.

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Abbreviations

HePC:

hexadecylphosphorylcholine

PLD:

phospholipase D

PKC:

protein kinase C

PI-PLC:

PI-specific phospholipase C

PIP2:

phosphatidylinositol 4,5-bisphosphate

IP3:

inositol trisphosphate

DAG:

diacylglicerol

PC:

phosphatidylcholine

Cho:

choline

PA:

phosphatidic acid

LPA:

lysophosphatidic acid

PAH:

phosphatidic acid hydrolase

PCho:

phosphorylcholine

DMEM:

Dulbecco's modified Eagle's medium

MDCK:

Madin-Darby Canine Kidney epithelial cells

PDBu:

Phorbol 12,13-dibutyrate

PtdBut:

phosphatidylbutanol

PDGF:

platelet derived growth factor

FGF:

fibroblast growth factor

ChoK:

choline kinase

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Acknowledgements

We are grateful to Dr MA Frohman for PLD1 and PLD2 plasmids. This work was supported by the following grants: SAF98-112-C02-01 from DGESIC, 08.1/45.1/98 from Consejería de Educación of Comunidad de Madrid, FIS 99/817, FEDER 2FD97-647 and 2FD97-1569. V Penalva is a fellow from Comunidad de Madrid. R Hernández-Alcoceba was supported by a fellowship of Fundación Ramón Areces.

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  1. Rubén Hernández-Alcoceba

    Present address: University of Michigan, USA

Authors and Affiliations

  1. Instituto de Investigaciones Biomédicas, CSIC, Madrid, Spain

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

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Lucas, L., Hernández-Alcoceba, R., Penalva, V. et al. Modulation of phospholipase D by hexadecylphosphorylcholine: a putative novel mechanism for its antitumoral activity. Oncogene 20, 1110–1117 (2001). https://doi.org/10.1038/sj.onc.1204216

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