Regulation of phosphatidylcholine biosynthesis by mitogenic growth factors

Warden, Craig H; Friedkin, Morris

doi:10.1016/0005-2760(84)90194-2

Cited by 79 publications

(55 citation statements)

References 24 publications

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“…Carcinogens such as polycyclic aromatic hydrocarbons and 1,2-dimethylhydrazine induce liver and colon cancers with increased Chk activity (17). Chk can also be induced by activating agents including hormones, growth factors, oncogenes, and carcinogens (19)(20)(21). Because of its increased expression and activity in cancer, Chk has been proposed as a target for antitumor therapy (16,22,23).…”

Section: Introductionmentioning

confidence: 99%

Choline Kinase Down-regulation Increases the Effect of 5-Fluorouracil in Breast Cancer Cells

et al. 2007

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Identifying strategies to increase cancer cell kill while sparing normal tissue is critically important in cancer chemotherapy. Choline kinase (Chk), the enzyme that converts choline to phosphocholine (PC), is elevated in cancer cells and presents a novel target for increasing cell kill. Here, we have examined the effects of transiently down-regulating Chk by small interfering RNA against Chk (siRNA-chk) on PC and total choline-containing compound (tCho) levels and on the viability/proliferation of estrogen receptor-negative and estrogen receptor-positive breast cancer cell lines and a nonmalignant mammary epithelial cell line. We investigated the effects of combination treatment with transient siRNAchk transfection and the anticancer drug 5-fluorouracil (5-FU) in those cell lines. Microarray analysis of the invasive estrogen receptor-negative MDA-MB-231 cell line was done to characterize molecular changes associated with Chk downregulation. Chk down-regulation decreased PC and tCho levels in the malignant cell lines, whereas the cell viability/ proliferation assays detected a decrease in proliferation in these cells. In contrast, Chk down-regulation had an almost negligible effect on PC and tCho levels as well as cell viability/proliferation in the nonmalignant cell line. A combination of siRNA-chk with 5-FU treatment resulted in a larger reduction of cell viability/proliferation in the breast cancer cell lines; this reduction was evident to a much lesser degree in the nonmalignant cells. Microarray analysis showed that Chk down-regulation affected 33 proliferation-related genes and 9 DNA repair-related genes. Chk down-regulation with siRNA-chk may provide a novel alternative to enhance the effect of anticancer drugs in malignant cells. [Cancer Res 2007;67(23):11284-90]

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Section: Introductionmentioning

confidence: 99%

Choline Kinase Down-regulation Increases the Effect of 5-Fluorouracil in Breast Cancer Cells

et al. 2007

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“…Since increased phospholipid synthesis indeed accompanies stimulated cell growth [6], it is difficult to provide evidence that water-soluble intermediates of phospholipid metabolism also affect mitogenesis by an independent mechanism. Such evidence would include the demonstration that a portion of mitogenic activity of phospholipid intermediates is not accompanied by increased phospholipid synthesis.…”

Section: Introductionmentioning

confidence: 99%

Ethanolamine analogues stimulate DNA synthesis by a mechanism not involving phosphatidylethanolamine synthesis

Kiss

Crilly

1996

FEBS Letters

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Dimethylethanolamine (0.5-1 mM), added to serumstarved N1H 3T3 fibroblasts, stimulated DNA synthesis 11-32-fold, and it also greatly enhanced the relatively modest (15-20-fold) mitogenic effect of insulin. Ethanolamine and momomethylethanolamine alone had no effects on DNA synthesis, but they also enhanced the stimulatory effect of insulin, although less effectively than dimethylethanolamine did. Lower concentrations (2.5-5 ~tglml) of compound D 609 (tricyclo-9-yl-xanthogenate), which had no effects on phospholipase activities, synergistically enhanced the combined effects of ethanolamine analogs and insulin on DNA synthesis without affecting the synthesis of ethanolamine phospholipids. These results suggest that ethanolamine and its analogues, formed by phospholipase D-mediated hydrolysis of ethanolamine phospholipids, may have growth regulatory functions independent of their role as phospholipid precursors.

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“…21,22) In addition, phosphocholine has been shown to promote growth in NIH3T3 fibroblast cells. [22][23][24] Furthermore, nuclear magnetic resonance (NMR) spectroscopy has demonstrated higher concentrations of phosphocholine in human tumor tissues and growth-promoted cells. [25][26][27][28][29] These results suggest that phosphocholine and choline kinase may not only play a role in phospholipid synthesis, but also in regulating cellular growth in cancer cells.…”

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confidence: 99%

Increased Choline Kinase Activity and Elevated Phosphocholine Levels in Human Colon Cancer^†

Nakagami

Uchida

Ohwada

et al. 1999

Japanese Journal of Cancer Research

112

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Nuclear magnetic resonance spectroscopy has detected elevated phosphocholine levels in human tumor tissues and cells, and in cells that were transformed with the activated Ha-ras gene and stimulated in vitro with growth-promoting factors such as platelet-derived growth factor, epidermal growth factor, and phorbol ester. However, the mechanism of the elevation and the function of the increased phosphocholine levels have not been clearly demonstrated. We studied phosphocholine levels enzymatically and analyzed the activity of choline kinase, which catalyzes the phosphorylation of choline to produce phosphocholine, in human colon cancer and adenoma. Both choline kinase activity and phosphocholine levels were increased in colon cancer and adenoma tissue. The activation of choline kinase and the increased levels of choline kinase α α α α were partly responsible for the elevated phosphocholine levels. This study suggests that choline kinase might play a role in growth promotion or signal transduction in carcinogenesis.Key words: Choline kinase -Phosphocholine -Human colon cancerCancer of the colon is one of the most common cancers in developed countries and its prevention is of great interest throughout the world. It is thought that the accumulation of certain mutated genes, including oncogenes, tumor suppressor genes, genes for DNA-repair enzymes, and invasion/metastasis-related genes, is necessary for the onset and progression of cancer. Mutation may cause further malignant changes in cellular proliferation, especially in enzymatic properties and activity.1-3) Some of the changes in enzymatic properties and activity with proliferation may be advantageous to the cancer cells. [4][5][6][7] Studying the cellular properties of cancer cells improves our understanding of the mechanism of cellular growth control and sheds further light on cancer prevention and treatment. 8) Choline kinase is the first enzyme in the cytidine 5′-diphosphate (CDP)-choline pathway for the synthesis of phosphatidylcholine, and phosphorylates choline to phosphocholine using adenosine 5′-triphosphate (ATP) as the phosphate donor. [9][10][11] In vitro studies of oncogenic ras proteins, and products and growth factors have shown that phosphocholine contributes to cellular growth regulation and intracellular signal transduction. Ras proteins play a pivotal role in cellular signal transduction, and help regulate cellular proliferation and terminal differentiation. [12][13][14] Microinjecting the oncogenic Ha-ras gene product p21 ras into Xenopus oocytes causes meiosis, 15) quickly activates choline kinase and elevates phosphocholine levels. 16)Transforming fibroblastic cells with oncogenic Ha-ras also activates choline kinase. [17][18][19] Growth factors essential for cellular growth also activate choline kinase, elevating the intracellular phosphocholine level. Prolactin is one such growth factor for Nb 2 rat node lymphoma cells.20) It has been suggested that platelet-derived growth factor might use a choline kinase-phosphocholine route to promote c...

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Regulation of phosphatidylcholine biosynthesis by mitogenic growth factors

Cited by 79 publications

References 24 publications

Choline Kinase Down-regulation Increases the Effect of 5-Fluorouracil in Breast Cancer Cells

Choline Kinase Down-regulation Increases the Effect of 5-Fluorouracil in Breast Cancer Cells

Ethanolamine analogues stimulate DNA synthesis by a mechanism not involving phosphatidylethanolamine synthesis

Increased Choline Kinase Activity and Elevated Phosphocholine Levels in Human Colon Cancer^†

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Regulation of phosphatidylcholine biosynthesis by mitogenic growth factors

Cited by 79 publications

References 24 publications

Choline Kinase Down-regulation Increases the Effect of 5-Fluorouracil in Breast Cancer Cells

Choline Kinase Down-regulation Increases the Effect of 5-Fluorouracil in Breast Cancer Cells

Ethanolamine analogues stimulate DNA synthesis by a mechanism not involving phosphatidylethanolamine synthesis

Increased Choline Kinase Activity and Elevated Phosphocholine Levels in Human Colon Cancer†

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Increased Choline Kinase Activity and Elevated Phosphocholine Levels in Human Colon Cancer^†