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PubMed1977

Studies on Sequential Parasitism by Orobanche and Cuscuta on Petunia hybrida: Choline Kinase and Phospholipid.

Parasitism by Cuscuta and Orobanche on Petunia hybrida resulted in decreased choline kinase activity and phospholipids in the host shoots. The Cuscuta-infected host roots suffered a decline in phospholipid concentration with no appreciable change in enzyme activity, whereas the roots of the Orobanche-infected plants exhibited a substantial increase in phospholipid concentration despite a marked lowering in enzymic activity. Superimposition of infection by Cuscuta on Orobanche-infected plants resulted in an increase in both enzyme activity and phospholipid in host shoots; the host roots recorded a decline in phospholipid, although enzyme activity was increased. As compared to the filaments infecting singly, Cuscuta, in sequential infection, registered an increase in phospholipid concomitant with a fall in enzyme activity, whereas the root parasite revealed a lowered enzyme activity and a slight decrease in phospholipid. It is hypothesized that a physiological response to infection by root parasite was an accumulation of phospholipids at the region under infection, and to that by shoot parasite was an uptake of phospholipids by the parasite from the host; this was effected not by de novo synthesis but rather by mobilization from distal regions.

Journal Article↗
PubMed1996

Stimulation of phospholipid synthesis in HeLa cells by epidermal growth factor and insulin: activation of choline kinase and glycerophosphate acyltransferase.

The cultivation of HeLa cells in the absence of growth factors reduced proliferation with a considerable decrease in the phospholipid content. A single addition of EGF or insulin was not enough to stimulate proliferation, but still sufficient to efficiently restore the phospholipid content to the level of serum-grown cells. Both EGF and insulin stimulated the synthesis of major phospholipids in HeLa cells. Irrespective of whether cells were stimulated or not, the phospholipid composition and the phospholipid/protein ratio remained constant, suggesting the existence of a mechanism that keeps them constant under varying conditions. The degradation of phosphatidylcholine was not affected by EGF or insulin. Both EGF and insulin increased choline kinase activity equally and promoted the conversion of choline to cholinephosphate, accompanied by an expansion of the cholinephosphate pool in treated cells. The level of glycerophosphate acyltransferase was enhanced by EGF and insulin but EGF was more effective than insulin. The present results provide evidence that one of the roles of EGF and insulin during cell growth is to stimulate the synthesis of phospholipids.

Choline↗
PubMed2001

LUMO energy of model compounds of bispyridinium compounds as an index for the inhibition of choline kinase.

Eleven derivatives of 1,1'-[1,2-ethylenebis(benzene-1,4-diylmethylene)]bis(4-pyridinium) dibromides bearing various groups at C-4 of the pyridinium moiety were synthesized and examined for their inhibition of choline kinase (ChoK) and antiproliferative activities. The C-4 substituents include electron-releasing, neutral or electron-withdrawing groups. A one-parameter regression equation has been derived which satisfactorily describes the ex vivo inhibitory potency of ChoK of the title compounds. The electronic effect plays a critical function in the ex vivo inhibition of ChoK although the role of electrostatic interactions could be altered due to a solvation process of both ChoK and ligands.

Choline Kinase↗
PubMed1999

Mechanisms underlying the transfer of phosphorylcholine to filarial nematode glycoproteins--a possible role for choline kinase.

Phosphorylcholine (PC) is a common constituent of proteins secreted by filarial nematodes. As this substance has been shown to interfere with immune responses, we are interested in designing strategies for blocking its attachment. Towards this end, we are investigating the mechanism of incorporation of PC into filarial molecules and in the present manuscript we describe experiments relating to elucidating the source of PC for attachment. Synthesis of phosphatidylcholine in eukaryotic organisms can occur by a mechanism involving the transfer of PC from CDP-choline to diacylglycerol (the Kennedy pathway). By (i) measuring transfer of radio-isotope labelled PC from CDP-choline to parasite molecules and (ii) employing inhibitors of CDP-choline synthesis, we have investigated whether CDP-choline can act as a source of PC for transfer to ES-62, a major secreted glycoprotein of the rodent filarial nematode Acanthocheilonema viteae. Although we can find no evidence of this, we show that attachment of PC is blocked by hemicholinium-3, an inhibitor of choline kinase, the first enzyme in the Kennedy pathway. Thus, at least the first step in this pathway--phosphorylation of choline, would appear to be necessary for attachment of PC to ES-62.

Animals↗
PubMed2004

Choline kinase activation is a critical requirement for the proliferation of primary human mammary epithelial cells and breast tumor progression.

Breast cancer is still one of the most important tumors among women in industrialized countries. Improvement in both understanding the molecular events associated with the disease and the development of new additional treatments is still an important goal to be achieved. Choline kinase (ChoK) is increased in human mammary tumors with high incidence, and this activation is associated with clinical variable indicators of greater malignancy. Here, we have investigated the role of ChoK in the development of breast cancer and found that ChoK is both necessary and sufficient for growth factor-induced proliferation in primary human mammary epithelial cells and an absolute requirement for the specific mitogenic response to heregulin in breast tumor-derived cells. These results demonstrate that ChoK plays an essential role in both normal human mammary epithelial cell proliferation and breast tumor progression. Furthermore, inhibition of ChoK shows a strong in vivo antitumor activity against human breast cancer xenografts. Thus, ChoK constitutes a novel bona fide molecular target for the treatment of breast cancer patients.

Animals↗
PubMed2003

Inhibition of choline kinase as a specific cytotoxic strategy in oncogene-transformed cells.

Cancer treatment is in the need of selective drugs that can interfere specifically with signalling pathways affected during the carcinogenic process. Identification of new potential molecular targets is the key event in the design of new anticancer strategies. Once identified, attempts for the generation of specific molecules to regulate their function can be achieved. The relevance of deregulation of choline kinase (ChoK, E.C. 2.7.1.32) in oncogene-driven cell transformation has been previously demonstrated. Here we provide strong evidence that MN58b, a selective inhibitor of ChoK, is rather specific to this enzyme, with no effect on a variety of oncogene-activated signalling pathways involved in the regulation of cell proliferation. MN58b does not affect MAPKs, PI3K, and other enzymes involved in the regulation of phospholipid metabolism such as phospholipases C, D, and A2, CTP:phosphocholine cytidylyltransferase, or diacylglycerol choline-phosphotransferase. Consistent with this specificity, ectopic expression of ChoK resulted in resistance to its inhibitor. Finally, nontransformed cells were able to resume cell proliferation after removal of the drug, while transformed cells were irreversibly affected. These results indicate that inhibition of ChoK is a rather specific strategy for the cytotoxic treatment of transformed cells.

Animals↗
PubMed2003

Choline kinase inhibitory effect and antiproliferative activity of new 1,1',1"-(benzene-1,3,5-triylmethylene)tris[4-[(disubstituted)amino]pyridinium] tribromides.

Four derivatives of 1,1'-(benzene-1,3-diylmethylene)bis[4-[(disubstituted)amino]-pyridinium] dibromides (2-5) and six derivatives of 1,1',1"-(benzene-1,3,5-triylmethylene)-tris[4-[(disubstituted)amino]pyridinium] tribromides (6-11) were synthesised and examined for their inhibition of human choline kinase (ChoK) and antiproliferative activities. The latter are more potent as ChoK inhibitors than the former, but the antiproliferative activities against the HT-29 cell line show the opposite tendency. The higher affinity of the trispyridinium compared with the bispyridinium ones may be due to direct binding of the third pyridinium group to ChoK or may arise from a reduction of the unfavourable entropy of binding via an increase of the 'local concentration' of pyridinium groups.

Antineoplastic Agents↗
PubMed1989

Elevated phosphocholine concentration in ras-transformed NIH 3T3 cells arises from increased choline kinase activity, not from phosphatidylcholine breakdown.

The cellular concentration of phosphocholine has been reported to be significantly elevated in Ha-ras-transformed NIH 3T3 cells, but not in v-sis transformants (J. C. Lacal, J. Moscat, and S. A. Aaronson, Nature [London] 330:269-271, 1987). It was suggested that the phosphocholine arises from constitutive hydrolysis of phosphatidylcholine by phospholipase C, an activity that would also account for the elevated 1,2-diacylglycerol found in ras-transformed cells. I have demonstrated that the increased phosphocholine arises through the induction of choline kinase activity. No increased breakdown of phosphatidylcholine was observed in ras-transformed cells. The elevation in diacylglycerol is therefore unlikely to be a consequence of phosphatidylinositol or phosphatidylcholine turnover.

Cell Line, Transformed↗
PubMed2003

Phospholipase D and choline kinase: their role in cancer development and their potential as drug targets.

Malignant cells result from the accumulation of genetic alterations that impinge into the components of signal transduction pathways controlling cell growth, differentiation and apoptosis. One of the critical pathways is related to the regulation of the phospholipid homeostasis. The identification of the molecular components involved in normal cell growth regulation altered upon transformation is required for the development of chemotherapeutic interventions against transformed cells. Discovery of new chemotherapeutic agents is one of the most promising ways to improve our success against cancer, and rational drug design is a key factor to achieve this goal. Evidence supporting choline kinase and phospholipase D as such novel targets is provided.

Animals↗
PubMed2002

Overexpression of choline kinase is a frequent feature in human tumor-derived cell lines and in lung, prostate, and colorectal human cancers.

Carcinogenesis is a long process that results in the accumulation of genetic alterations primarily in genes involved in the regulation of signalling pathways relevant for the regulation of cell growth and the cell cycle. Alteration of additional genes regulating cell adhesion and migration, angiogenesis, apoptosis, and drug resistance confers to the cancer cells a more malignant phenotype. Genes that participate in the regulation of some critical metabolic pathways are also altered during this process. Choline kinase (ChoK) has been reported to belong to the latter family of cancer-related genes. Recently, we have reported that increased activity of ChoK is observed in human breast carcinomas. Here, we provide further evidence that ChoK dysregulation is a frequent event found in a variety of human tumors such as lung, colorectal, and prostate tumors. Furthermore, a large panel of human tumor-derived cell lines also show increased ChoK activity when compared to appropriate non-tumorigenic or primary cells. These findings strongly support the role of ChoK alterations in the carcinogenic process in human tumors, suggesting that ChoK could be used as a tumor marker.

Adult↗
PubMed1997

Choline kinase inhibitors as a novel approach for antiproliferative drug design.

Recent progress in deciphering the molecular basis of carcinogenesis is of utmost importance to the development of new anticancer strategies. To this end, it is essential to understand the regulation of both normal cell proliferation and its alterations in cancer cells. We have previously demonstrated that in ras-transformed cells there is an increased level of phosphorylcholine (PCho) resulting from a constitutive activation on choiline kinase (ChoK). The importance of ChoK for the regulation of cell proliferation has also been proposed since an inhibitor for this enzyme, hemicholinium-3 (HC-3), drastically reduces entry into the S phase after stimulation with growth factors. Here we report the synthesis of several new compounds which are highly specific inhibitors for ChoK, with up to 1000-fold or 600-fold increased inhibitory activity, compared to HC-3 under ex vivo or in vitro conditions respectively. These novel compounds also drastically reduce entry into the S phase after stimulation with specific growth factors. A more profound inhibition of cell proliferation was observed in ras-, src- and mos-transformed cells in the presence of ChoK inhibitors, compared to their parental, untransformed NIH3T3 cells. By contrast, this effect was not observed in fos-transformed cells. While ras, src and mos transformation is associated with elevated levels of ChoK activity, fos-induced transformation does not affect ChoK activity. The inhibitory effect on proliferation of the new compounds correlates with their ability to inhibit the production of phosphorylcholine in whole cells, a proposed novel second messenger for cell proliferation. These results strongly support a critical role of choline kinase in the regulation of cell growth and makes this enzyme a novel target for the design of new antiproliferative and anticancer drugs.

3T3 Cells↗
PubMed2001

Choline kinase: a novel target for antitumor drugs.

Malignant cells are characterized by the accumulation of genetic alterations, which result in the disregulation of signal transduction pathways that control proliferation, differentiation and apoptosis. The identification of the molecular components involved in these aberrant processes is necessary for the development of chemotherapeutic interventions to restore or selectively destroy the transformed cells. Discovery of new chemotherapeutic agents is probably one of the most reliable ways to improve our success against cancer, and intelligent drug design is a key factor to achieve this goal. Thus, the identification of novel targets for anticancer drug discovery is needed. This review provides evidence to support choline kinase as one such target.

Journal Article↗