Metabolic changes underlying31P MR spectral alterations in human hepatic tumours

Bell, Jimmy D.; Bhakoo, Kishore

doi:10.1002/(sici)1099-1492(1998110)11:7<354::aid-nbm515>3.0.co;2-n

Cited by 42 publications

(9 citation statements)

References 31 publications

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“…The results from these studies and our observations suggest that up-regulation of CHKA and PCYT1A in HBV replicating cells could contribute to the HCC induced by chronic HBV infection. This notion is reinforced by the close association between CHKA overexpression and increased levels of PCho and PC, with oncogenesis, in cells, animals and patients 39 40 41 . In addition, HBV replication could induce oxidative stress through producing more reactive oxygen species (ROS) 6 42 .…”

Section: Discussionmentioning

confidence: 98%

The metabolic responses to hepatitis B virus infection shed new light on pathogenesis and targets for treatment

Zhu

Zhang

et al. 2015

Sci Rep

125

115

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Chronic infection caused by the hepatitis B virus (HBV), is strongly associated with hepatitis, fatty liver and hepatocellular carcinoma. To investigate the underlying mechanisms, we characterize the metabolic features of host cells infected with the virus using systems biological approach. The results show that HBV replication induces systematic metabolic alterations in host cells. HBV infection up-regulates the biosynthesis of hexosamine and phosphatidylcholine by activating glutamine-fructose-6-phosphate amidotransferase 1 (GFAT1) and choline kinase alpha (CHKA) respectively, which were reported for the first time for HBV infection. Importantly suppressing hexosamine biosynthesis and phosphatidylcholine biosynthesis can inhibit HBV replication and expression. In addition, HBV induces oxidative stress and stimulates central carbon metabolism and nucleotide synthesis. Our results also indicate that HBV associated hepatocellular carcinoma could be attributed to GFAT1 activated hexosamine biosynthesis and CHKA activated phosphatidylcholine biosynthesis. This study provides further insights into the pathogenesis of HBV-induced diseases, and sheds new light on drug target for treating HBV infection.

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Section: Discussionmentioning

confidence: 98%

The metabolic responses to hepatitis B virus infection shed new light on pathogenesis and targets for treatment

Zhu

Zhang

et al. 2015

Sci Rep

125

115

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“…An increase in CCT activity would therefore result in the depletion of cellular PCho levels. However, 31 P MRS has frequently demonstrated that liver tumours contain significantly increased cellular PCho levels compared with normal liver 49 . Because several enzymes, other than CCT, such as CHK and PtdCho-specific phospholipase C (PC-PLC), can increase intracellular PCho levels, these enzymes may counteract a possible depletion of cellular PCho levels by increased CCT activity in liver tumorigenesis (TABLE 1).…”

Section: Key Enzymes In Choline Metabolism In Cancermentioning

confidence: 99%

Choline metabolism in malignant transformation

2011

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Abnormal choline metabolism is emerging as a metabolic hallmark that is associated with oncogenesis and tumour progression. Following transformation, the modulation of enzymes that control anabolic and catabolic pathways causes increased levels of choline-containing precursors and breakdown products of membrane phospholipids. These increased levels are associated with proliferation, and recent studies emphasize the complex reciprocal interactions between oncogenic signalling and choline metabolism. Because choline-containing compounds are detected by non-invasive magnetic resonance spectroscopy (MRS), increased levels of these compounds provide a non-invasive biomarker of transformation, staging and response to therapy. Furthermore, enzymes of choline metabolism, such as choline kinase, present novel targets for image-guided cancer therapy.

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“…Furthermore, high levels of PCho have been found in tumoral cells as well as in tumour samples of cancer patients compared with the normal counterparts in breast, prostate, brain and ovarian cancer [19]–[25]. The increase in phosphoethanolamine has been also reported in transformed cells or tumor samples using MRS, although it contributes to a much lesser extent, compared with the increase of PCho, to the phosphomonoester peak [26].…”

Section: Introductionmentioning

confidence: 99%

Differential Role of Human Choline Kinase α and β Enzymes in Lipid Metabolism: Implications in Cancer Onset and Treatment

et al. 2009

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BackgroundThe Kennedy pathway generates phosphocoline and phosphoethanolamine through its two branches. Choline Kinase (ChoK) is the first enzyme of the Kennedy branch of synthesis of phosphocholine, the major component of the plasma membrane. ChoK family of proteins is composed by ChoKα and ChoKβ isoforms, the first one with two different variants of splicing. Recently ChoKα has been implicated in the carcinogenic process, since it is over-expressed in a variety of human cancers. However, no evidence for a role of ChoKβ in carcinogenesis has been reported.Methodology/Principal FindingsHere we compare the in vitro and in vivo properties of ChoKα1 and ChoKβ in lipid metabolism, and their potential role in carcinogenesis. Both ChoKα1 and ChoKβ showed choline and ethanolamine kinase activities when assayed in cell extracts, though with different affinity for their substrates. However, they behave differentially when overexpressed in whole cells. Whereas ChoKβ display an ethanolamine kinase role, ChoKα1 present a dual choline/ethanolamine kinase role, suggesting the involvement of each ChoK isoform in distinct biochemical pathways under in vivo conditions. In addition, while overexpression of ChoKα1 is oncogenic when overexpressed in HEK293T or MDCK cells, ChoKβ overexpression is not sufficient to induce in vitro cell transformation nor in vivo tumor growth. Furthermore, a significant upregulation of ChoKα1 mRNA levels in a panel of breast and lung cancer cell lines was found, but no changes in ChoKβ mRNA levels were observed. Finally, MN58b, a previously described potent inhibitor of ChoK with in vivo antitumoral activity, shows more than 20-fold higher efficiency towards ChoKα1 than ChoKβ.Conclusion/SignificanceThis study represents the first evidence of the distinct metabolic role of ChoKα and ChoKβ isoforms, suggesting different physiological roles and implications in human carcinogenesis. These findings constitute a step forward in the design of an antitumoral strategy based on ChoK inhibition.

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Metabolic changes underlying31P MR spectral alterations in human hepatic tumours

Cited by 42 publications

References 31 publications

The metabolic responses to hepatitis B virus infection shed new light on pathogenesis and targets for treatment

The metabolic responses to hepatitis B virus infection shed new light on pathogenesis and targets for treatment

Choline metabolism in malignant transformation

Differential Role of Human Choline Kinase α and β Enzymes in Lipid Metabolism: Implications in Cancer Onset and Treatment

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