Alterations of Choline Phospholipid Metabolism in Ovarian Tumor Progression (original) (raw)
Related papers
Magnetic …, 1997
The results of an initial study on the feasibility of using the phosphonium analog of choline to follow the metabolism of phosphatidylcholine in tumors in vivo using 31P NMR are reported. C3HIHe mice bearing a mammary carcinoma tumor on the foot pad were fed a choline-free diet supplemented with the phosphonium analog of choline. Metabolites of this compound, including the phosphonium analogs of phosphatidylcholine, phosphocholine, glycerophosphocholine, and betaine were observed noninvasively in vivo in tumors by 31P NMR after 2-3 weeks of feeding. Clearance of these phosphonium-labeled metabolites from tumors was measured after a change to a choline-containing diet. Significant decreases were seen in the levels of the analogs of betaine (P < 0.003) and phosphatidylcholine (P < 0.004) by Day 4. A significant increase in the level of authentic phosphocholine (P < 0.003) occurred over the same time period.
Choline Metabolism Alteration: A Focus on Ovarian Cancer
Frontiers in oncology, 2016
Compared with normal differentiated cells, cancer cells require a metabolic reprograming to support their high proliferation rates and survival. Aberrant choline metabolism is a fairly new metabolic hallmark reflecting the complex reciprocal interactions between oncogenic signaling and cellular metabolism. Alterations of the involved metabolic network may be sustained by changes in activity of several choline transporters as well as of enzymes such as choline kinase-alpha (ChoK-α) and phosphatidylcholine-specific phospholipases C and D. Of note, the net outcome of these enzymatic alterations is an increase of phosphocholine and total choline-containing compounds, a "cholinic phenotype" that can be monitored in cancer by magnetic resonance spectroscopy. This review will highlight the molecular basis for targeting this pathway in epithelial ovarian cancer (EOC), a highly heterogeneous and lethal malignancy characterized by late diagnosis, frequent relapse, and development of...
Activation of Phosphatidylcholine Cycle Enzymes in Human Epithelial Ovarian Cancer Cells
Cancer Research, 2010
Altered phosphatidylcholine (PC) metabolism in epithelial ovarian cancer (EOC) can provide choline-based imaging approaches as powerful tools to improve diagnosis and identify new therapeutic targets. The increase in the major choline-containing metabolite phosphocholine (PCho) in EOC compared with normal and non-tumoral immortalized counterparts (EONT), may derive from a) enhanced choline transport and choline kinase (ChoK)-mediated phosphorylation; b) increased PC-specific phospholipase C (PC-plc) activity; c) increased intracellular choline production by PC deacylation plus glycerophosphocholine-phosphodiesterase (GPC-pd) or by phospholipase D (pld)-mediated PC catabolism, followed by choline phosphorylation. Biochemical, protein and mRNA expression analyses demonstrated that the most relevant changes in EOC cells were: 1) 12-to 25-fold ChoK activation, consistent with higher protein content and increased ChoKα (but not ChoKβ) mRNA expression levels; 2) 5-to 17-fold PC-plc activation, consistent with higher, previously reported, protein expression. PC-plc inhibition by tricyclodecan-9-yl-potassium xanthate (D609) induced in OVCAR3 and SKOV3 cancer cells a 30-to-40% reduction of PCho content and blocked cell proliferation. More limited and variable sources of PCho could derive, in some EOC cells, from 2-to 4-fold activation of pld or GPC-pd. Phospholipase A2 activity and isoforms' expression levels were lower or unchanged in EOC compared with EONT cells. Increased ChoKα mRNA, as well as ChoK and PC-plc protein expression, were also detected in surgical specimens isolated from EOC patients. Overall, we demonstrated that the elevated PCho pool detected in EOC cells primarily resulted from upregulation/activation of ChoK and PC-plc involved in the biosynthetic and in a degradative pathway of the PC-cycle, respectively.
2002
Specific genetic alterations during malignant transformation may induce the synthesis and breakdown of choline phospholipids, mediating transduction of mitogenic signals. The high level of water-soluble choline metabolites in cancerous breast tumors, relative to benign lesions and normal breast tissue, has been used as a diagnostic marker of malignancy. To unravel the biochemical pathways underlying this phenomenon, we used tracer kinetics and 13C and 31P magnetic resonance spectroscopy to compare choline transport, routing, and metabolism to phospholipids in primary cultures of human mammary epithelial cells and in MCF7 human breast cancer cells. The rate of choline transport under physiological choline concentrations was 2-fold higher in the cancer cells. The phosphorylation of choline to phosphocholine and oxidation of choline to betaine yielded 10-fold higher levels of these metabolites in the cancer cells. However, additional incorporation of choline to phosphatidylcholine was ...
Current Medical Imaging Reviews, 2007
Elevated contents of choline phospholipid metabolites are typically detected by nuclear magnetic resonance spectroscopy (MRS) in human and animal tumors. An increase in the intensity of the 1 H-MRS profile of total cholinecontaining compounds (tCho, 3.2 ppm) is today considered as a common feature in different types of cancer, beyond their otherwise wide phenotypic variability. This finding fostered investigations on the molecular mechanisms underlying the observed spectral changes and on correlations between aberrant phospholipid metabolism and tumor progression. At the clinical level, efforts are addressed to evaluate effectiveness and potential use of in vivo localized MRS and choline-based positron emission tomography (Cho-PET) in cancer diagnosis. Aims of this article are: a) to overview recent advances in the identification of biochemical pathways responsible for the altered 1 H-MRS tCho profile in breast and ovary cancer cells, as a basis for interpreting in vivo MR spectra and enhanced uptake of radiolabeled choline in PET; b) to summarize recent developments of in vivo 1 H-MRS methods in breast cancer diagnosis; c) to discuss the potentialities of complementing current diagnostic modalities with noninvasive MRS and Cho-PET methods to monitor biochemical alterations associated with progression, relapse and therapy response in ovary cancer.
Current Medical Imaging Reviews, 2007
Elevated contents of choline phospholipid metabolites are typically detected by nuclear magnetic resonance spectroscopy (MRS) in human and animal tumors. An increase in the intensity of the 1 H-MRS profile of total cholinecontaining compounds (tCho, 3.2 ppm) is today considered as a common feature in different types of cancer, beyond their otherwise wide phenotypic variability. This finding fostered investigations on the molecular mechanisms underlying the observed spectral changes and on correlations between aberrant phospholipid metabolism and tumor progression. At the clinical level, efforts are addressed to evaluate effectiveness and potential use of in vivo localized MRS and choline-based positron emission tomography (Cho-PET) in cancer diagnosis. Aims of this article are: a) to overview recent advances in the identification of biochemical pathways responsible for the altered 1 H-MRS tCho profile in breast and ovary cancer cells, as a basis for interpreting in vivo MR spectra and enhanced uptake of radiolabeled choline in PET; b) to summarize recent developments of in vivo 1 H-MRS methods in breast cancer diagnosis; c) to discuss the potentialities of complementing current diagnostic modalities with noninvasive MRS and Cho-PET methods to monitor biochemical alterations associated with progression, relapse and therapy response in ovary cancer.
Tumour phospholipid metabolism
NMR in Biomedicine, 1999
Abnormalities in phospholipid metabolism represent major hallmarks of cancer cells. Changes in the MRS profiles of aqueous precursors and catabolites of phosphatidylcholine (PtdCho) in cancer lesions allow non invasive monitoring of tumor progression and response to conventional and targeted anti-cancer therapies. Advances and limitations of our present understanding of molecular mechanisms underlying these anomalous metabolic profiles will be here discussed in the light of altered expression and activity of enzymes of the PtdCho cycle and links to dysregulated cell signaling pathways responsible for oncogenesis. An overview will also be provided of a) the role of choline metabolites as possible pharmacodynamic biomarkers of targeted therapies and b) current efforts to identify PtdCho cycle enzymes as possible targets for therapy.
Cancer research, 2000
De novo production of phosphatidic acid (PA) in tumor cells is required for phospholipid biosynthesis and growth of tumor cells. In addition, PA production by phospholipase D has been cited among the effects of certain oncogenes and growth factors. In this report, it has been demonstrated that enhanced phospholipid metabolism through PA in tumor cells can be exploited pharmacologically for development of anticancer agents, such as CT-2584, a cancer chemotherapeutic drug candidate currently in Phase II clinical trials. By inhibiting CTP:choline-phosphate cytidylyltransferase (CT), CT-2584 caused de novo phospholipid biosynthesis via PA to be shunted away from phosphatidylcholine (PC) and into phosphatidylinositol (PI), the latter of which was doubled in a variety of CT-2584-treated tumor cell lines. In contrast, cytotoxic concentrations of cisplatin did not induce accumulation of PI, indicating that PI elevation by CT-2584 was not a general consequence of chemotherapy-induced cell de...
Substantia, 2022
In the past 30 years there has been a significant increase in the number of publications on phospholipid (PL) metabolism, both for the medical purposes of detection and diagnosis of cancer and for the monitoring of the treatment of human cancers. Most of the work has focused on the pathway that produces phosphatidylcholine, the major component of human cell membranes. The trigger for this research was the advent of applications of NMR spectroscopy in vitro and in vivo in the 1980's and observations that most cancer cells and tumors had significant increases in the water-soluble PL precursors and breakdown products. Increased phosphocholine (PC) has been focused on as a marker for cancer using Magnetic Resonance Spectroscopy (MRS) and Positron Emission Tomography (PET). MRS is now used clinically to aid in the diagnosis and severity of some brain tumors; and choline PET is used for the diagnosis and staging of recurrent prostate cancer, paid for by medical insurance companies. Another major area of research starting in the 1990's was the development of specific choline kinase (CK) inhibitors aimed at the isoenzyme CK-a. This isoenzyme is markedly upregulated in cancer cells and unexpectedly was found to have a role in oncogenic transformation independent of its enzyme function.