The elevation of choline-containing metabolites [phosphocholine (PC), glycerophosphocholine (GPC), free choline (Cho)] and the over and under-expression of key enzymes in phospholipid membrane synthesis and degradation, specifically choline kinase
and a number of the phospholipases have been associated with the presence, progression and therapeutic response of a variety of human cancers including prostate.
Progression of human mammary epithelial cells from a normal to a malignant phenotype is associated with an induced overexpression of choline kinase (CK) that catalyzes the phosphorylation of choline to form phosphocoline, followed by generation of phosphatidylcholine in the tumour cell membranes (2).
Structure and function of choline kinase isoforms in mammalian cells.
Choline kinase activation is a critical requirement for the proliferation of primary human mammary epithelial cells and breast tumour progression.
Specifically, choline enters the cell via the choline transporter, being further phosphorylated to phosphatidylcholine by choline kinase
. Both of these molecules are upregulated in tumor cells, ultimately resulting in an enhanced choline uptake .
The genetic defects affect different proteins with essential roles in muscle development and function: defects of structural proteins (laminin-[alpha]2, collagen, integrin, and plectin), defects of glycosylation (Walker-Warburg syndrome, muscle-eye brain disease, and Fukuyama CMD), proteins of the endoplasmic reticulum and nucleus (selenoprotein, selenocysteine insertion sequence-binding protein 2, laminin A/C), and mitochondrial membrane protein (choline kinase
Raynaud et al., "The phosphoinositide 3-kinase inhibitor PI-103 downregulates choline kinase
a leading to phosphocholine and total choline decrease detected by magnetic resonance spectroscopy," Cancer Research, vol.