Choline phosphorylation and regulation of transcription of choline kinase α in hypoxia

Abstract

by choline kinase to form phosphocholine is the fi rst step of multistep Kennedy pathway ( 1 ) that synthesizes the major membrane phospholipid, phosphatidylcholine. Increased choline phosphorylation (primarily by choline kinase ␣ , ChK ␣ ) in tumor as compared with normal tissue has been reported in lung, breast, colorectal, and prostate cancers ( 2-5 ). This has motivated evaluation of cancer therapies involving choline kinase inhibition ( 6 ) and use of cancer imaging techniques with choline phosphorylation as a diagnostic metabolic step ( 7,8 ).Metabolism of choline in cancer cells is known to be sensitive to its microenvironment. Tracer studies in the mouse atrial cardiomyocyte tumor lineage, AT-1 ( 9 ), and 9L glioma allografts ( 10 ) showed that radiolabeled choline phosphorylation and accumulation is signifi cantly diminished in hypoxia. Our previous tracer studies with two human prostate cancer cell lines, PC-3 and LNCaP, showed 15% and 28% decreases in choline accumulation, respectively, after 4 h of anoxia (0% O 2 ) ( 11 ). After 24 h of anoxia, choline accumulation continued to decrease in both cell lines without loss of cellular viability. Because low oxygen exposure is a common factor in the microenvironment of tumors, it is important to understand the mechanisms of this effect and the implications for therapeutic and diagnostic applications involving choline metabolism.The goals of the present study were to utilize PC-3 prostate cancer cells to assess the effects of hypoxia on 1 ) steady-state levels of choline metabolites, 2 ) equilibrium status of choline phosphorylation, 3 ) radiolabeled choline uptake and phosphorylation, 4 ) ChK ␣ mRNA and protein levels, and 5 ) choline kinase activity. In this work, we demonstrate that choline phosphorylation is not at equilibrium In recent years, choline phospholipid metabolism has been widely studied in cancer research. Choline is an important precursor of phospholipids. Its phosphorylation

1H‐NMR‐based Metabolomic Study of Miamiensis avidus‐infected Olive Flounder

“…glucose and pyruvate) decreased in serum. Increased choline level might indicate that the serum milieu suffered severe hypoxia, resulting in a decreased choline kinase activity and choline phosphorylation . Leucine has been known as an activator of mTOR (mammalian target of rapamycin) signaling, which regulates diverse immune cells including neutrophils, mast cells, natural killer cells, macrophages, dendritic cells, T cells, and B cells .…”

Magnetic Resonance Spectroscopy for Detection of Choline Kinase Inhibition in the Treatment of Brain Tumors

“…However Bansal et al have reported a decrease in choline phosphorylation in hypoxic prostate cancer cells which may result from other isoforms of hypoxia response elements (HRE) affecting ChoK activity in human brain tumors. There is intensifying urgency to find new drugs for the treatment of brain tumors (47). Development of anticancer agents is the key focus of several research studies on developing specific molecular targets against the malignant phenotype (5, 48, 49) with the ultimate goal of improving activity and therapeutic selectivity for tumor versus normal cells.…”

Choline kinase alpha—Putting the ChoK-hold on tumor metabolism

“…This hepatotoxin was later found to cause upregulation of the oncogenic transcription factor c-jun that binds to an activator protein 1 (AP1) element site in the promoter region of CHKA [53]. Hypoxia response elements (HREs) in the CHKA promoter region have linked HIF1α activity to ChoKα expression [54,55]. Inhibitors of the mitochondrial electron transport chain in neuroblastoma cells can increase ChoKα expression and phospholipase activity, leading to elevated choline metabolites [56].…”