Increased Choline Kinase Activity in 1,2‐Dimethylhydrazine‐induced Rat Colon Cancer

Abstract

Cancer cells acquire particular characteristics that benefit their proliferation. We previously reported that human colon cancers examined had increased choline kinase activity and phosphocholine levels. The elevated phosphocholine levels were in part due to both activation of choline kinase and increased choline kinase α α α α protein levels. In this report, we analyzed choline kinase, which catalyzes the phosphorylation of choline to produce phosphocholine, in rat 1,2-dimethylhydrazine (DMH)-induced colon cancer. This study is the first to demonstrate increased choline kinase α α α α enzymatic activity, protein levels, and mRNA levels in DMH-induced colon cancer as well as human colon cancer, although phosphocholine was not increased in DMH-induced rat cancer. The increase in the mRNA level was partly due to an increase in the transcription of the choline kinase α α α α gene. The increased choline kinase activity may be a specific characteristic acquired by cancer cells that benefits their proliferation. Key words: Choline kinase -DMH -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 an accumulation of mutated genes, including oncogenes, tumor suppressor genes, DNA-repair enzyme genes, and invasion/ metastasis-related genes, is necessary for the generation and progression of cancer. Mutation may cause further malignant changes in cellular proliferation, 1) especially when enzymatic activity and properties are affected. 2-4)Some of the changes that occur in enzymatic properties and activity with proliferation may favor the growth of cancer cells. [5][6][7] Studying the cellular properties of cancer cells furthers our understanding of the mechanisms of cellular growth control and provides clues to strategies for cancer prevention and treatment. 8) 1,2-Dimethylhydrazine (DMH) is widely used for experimental studies of specific colon carcinogenesis in rodents. 9) In the body, the metabolic product of DMH modifies DNA, causes mutation, and leads to carcinogenesis. 10)Choline kinase is the first enzyme in the CDP-choline pathway for the synthesis of phosphatidylcholine, and phosphorylates choline to phosphocholine using adenosine 5′-triphosphate (ATP) as the phosphate donor.11, 12) Ras proteins play a pivotal role in cellular signal transduction, and help regulate cellular proliferation and terminal differentiation. [13][14][15] Microinjection of the oncogenic Ha-ras gene product p21 ras into Xenopus oocytes, which causes meiosis, 16) quickly elevates the phosphocholine level and activates choline kinase.17) Transformation of fibroblastic cells with oncogenic Ha-ras activates choline kinase. [18][19][20] Growth factors essential for cellular growth also activate choline kinase, elevating the intracellular phosphocholine level. It has been suggested that platelet-derived growth factor might use a choline kinase-phosphocholine route to promote cell growth in NIH3T3 fibroblast cells. [21][22][23][24] We pr...

Selenium as a chemopreventive agent in experimentally induced colon carcinogenesis

“…Therefore, the decreased lipid peroxidation observed in DMHtreated rats could be due to increased cell proliferation. The malignant tissues seem to be less susceptible and more resistant to free radical attack, and hence lipid peroxidation is less intense [35] . Interestingly, simultaneous selenium treatment to DMH treated animals showed an increase in the levels of MDA.The observed increased levels of LPO under selenium treatment could be as a consequence of the inhibitory action of selenium on the proliferative activity of cancerous cells.…”

RNA Interference–Mediated Choline Kinase Suppression in Breast Cancer Cells Induces Differentiation and Reduces Proliferation

“…Overexpression and increased activity of choline kinase in malignant cells and tumors (1)(2)(3)(4)(5) and oncogene-mediated increase in the activity and basal levels of choline kinase (6-10) have been reported in several studies. Both increased enzymatic activity as well as overexpression of choline kinase correlated strongly with histologic tumor grade and negative estrogen receptor status in breast carcinomas (1).…”

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

“…Choline kinase (Chk), a cytosolic enzyme that catalyzes the phosphorylation of choline to form PC by ATP in the presence of magnesium (7), is one of three enzymes that, along with phosphatidylcholine-specific phospholipase C and CTP:phosphocholine cytidylyltransferase, can lead to increased PC levels (8,9). Increased expression of Chk has been observed in human lung, colon, prostate, and breast cancer as well as derived epithelial and hemopoietic cell lines (10)(11)(12)(13)(14)(15)(16)(17)(18). Carcinogens such as polycyclic aromatic hydrocarbons and 1,2-dimethylhydrazine induce liver and colon cancers with increased Chk activity (17).…”