Choline Kinase: An Important Target for Cancer

Abstract

Choline kinase (ChoK) is a cytosolic enzyme present in various tissues, which catalyzes the phosphorylation of choline to form phosphorylcholine (PCho) in the presence of ATP and magnesium. ChoK is important for the generation of two major membrane phospholipids, phosphatidylcholine (PC) and sphingomyelin (SM) and subsequently for the cell division. ChoK plays a vital role in cell signaling pathways and regulation of cell growth along with PCho involved in malignant transformation through ras oncogenes in different cancers such as breast, lung, colon, prostate, neuroblastoma, hepatic lymphomas, meningiomas and diverse murine tumours. The Ras effectors serine/threonine kinase (Raf-1), the Ral-GDP dissociation stimulator (Ral-GDS) and the phosphatidylinositol 3-kinase (PI3K) are involved in the activation of ChoK during tumorigenesis. ChoK gene induction seems to be associated with certain cell stress or cell defense. Nowadays, RNAi appear to be one of the most promising routes in the cancer therapy. The anticancer potential of both stable expression of siRNAs and their high sequence specificity by RNAi mediated suppression of oncogenic ras in human pancreatic carcinoma, human melanomas and ovarian cancer has been observed. It has an important role in sequence specific post-transcriptional gene silencing mechanism. Presently, the crystal structure of Caenorhabditis elegans choline kinase A-2 (ChoKA-2) is available, which may be useful for comparative modeling of human ChoK and further modeling studies. The present review aims at the general overview of importance, expression, structure, progress in molecular modeling, active site analysis and inhibitors of ChoK. It also highlights the recent role of ChoK in various types of Ras-dependent and Ras-independent carcinogenesis.

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).…”

Radiotracers Used in Nuclear Medicine for Prostate Cancer Diagnosis and Follow-Up

“…It enters into the cell by means of choline transporters and is the precursor for phospholipid biosynthesis, which is the main component of the cell membrane 29 . Some tumors, particularly the prostatic tumor, show an increase in cell membrane synthesis as a consequence of uncontrolled cell proliferation, which is driven by choline kinase overexpression.…”

Radiotrazadores empleados en medicina nuclear para el diagnóstico y seguimiento del cáncer de próstata

“…Entra en la célula a través de transportadores de colina y es el precursor para la biosíntesis de fosfolípidos, los cuales son componentes principales de la membrana celular 29 . Algunos tumores, particularmente el de próstata, presentan un incremento de la síntesis de membrana celular como consecuencia de la proliferación celular descontrolada, que está condicionada por la sobreexpresión de colina-cinasa.…”