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Published in: Magnetic Resonance Materials in Physics, Biology and Medicine 2/2019

Open Access 01-04-2019 | Research Article

CDP-choline accumulation in breast and colorectal cancer cells treated with a GSK-3-targeting inhibitor

Authors: Su Myat Phyu, Chih-Chung Tseng, Tim Andrew Davies Smith

Published in: Magnetic Resonance Materials in Physics, Biology and Medicine | Issue 2/2019

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Abstract

Purpose

Glycogen synthase kinase 3 (GSK3) is a key controlling element of many cellular processes including cell-cycle progression and recent studies suggest that GSK3 is a potential anticancer target. Changes in glucose metabolism associated with GSK3 inhibition may impact on lipid synthesis, whilst lipid metabolites can act as molecular response markers.

Methods

Here, SKBr3 breast and HCT8 colorectal cancer cells were treated with the GSK3 inhibitor SB216763, and [14C (U)] glucose and [3H] choline incorporation into lipids was determined. Cell extracts from treated cells were subject to 31P NMR spectroscopy.

Results

SB216763 treatment decreased choline incorporation into lipids and caused an accumulation of CDP-choline which was accompanied by decreased conversion of glucose into lipid components.

Conclusion

SB216763 profoundly inhibits phospholipid synthesis in cancer cells which demonstrate accumulation of CDP-choline detectable by 31P NMR spectroscopy. Metabolic changes in lipid metabolism present potential response markers to drugs targeting GSK3.
Literature
1.
go back to reference Embi N, Rylatt DB, Cohen P (1980) Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase. Eur J Biochem 107:519–527CrossRefPubMed Embi N, Rylatt DB, Cohen P (1980) Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase. Eur J Biochem 107:519–527CrossRefPubMed
2.
go back to reference Liu X, Yao Z (2016) Chronic over-nutrition and dysregulation of GSK3 in diseases. Nutr Metab 13:49CrossRef Liu X, Yao Z (2016) Chronic over-nutrition and dysregulation of GSK3 in diseases. Nutr Metab 13:49CrossRef
3.
go back to reference Majewski N, Nogueira V, Robet RB et al (2004) Akt inhibits apoptosis downstream of BID cleavage via a glucose-dependent mechanism involving mitochondrial hexokinases. Mol Cell Biol 24:730–740CrossRefPubMedPubMedCentral Majewski N, Nogueira V, Robet RB et al (2004) Akt inhibits apoptosis downstream of BID cleavage via a glucose-dependent mechanism involving mitochondrial hexokinases. Mol Cell Biol 24:730–740CrossRefPubMedPubMedCentral
4.
go back to reference Fleming IN, Andriu A, Smith TAD (2014) Early changes in [18F] FDG incorporation by breast cancer cells treated with trastuzumab in normoxic conditions: role of the Akt-pathway, glucose transport and HIF-1α. Breast Cancer Res Treat 144:241–248CrossRefPubMed Fleming IN, Andriu A, Smith TAD (2014) Early changes in [18F] FDG incorporation by breast cancer cells treated with trastuzumab in normoxic conditions: role of the Akt-pathway, glucose transport and HIF-1α. Breast Cancer Res Treat 144:241–248CrossRefPubMed
5.
go back to reference Eldar-Finkelman H (2002) Glycogen synthase kinase 3: an emerging therapeutic target. Trends Mol Med 8:126–132CrossRefPubMed Eldar-Finkelman H (2002) Glycogen synthase kinase 3: an emerging therapeutic target. Trends Mol Med 8:126–132CrossRefPubMed
7.
go back to reference Domoto T, Pyko IY, Furuta T et al (2016) Glycogen synthase kinase-3 is a pivotal mediator of cancer invasion and resistance to therapy. Cancer Sci 107:1363–1372CrossRefPubMedPubMedCentral Domoto T, Pyko IY, Furuta T et al (2016) Glycogen synthase kinase-3 is a pivotal mediator of cancer invasion and resistance to therapy. Cancer Sci 107:1363–1372CrossRefPubMedPubMedCentral
8.
go back to reference Kotliarova S, Pastorino S, Kovell LC et al (2008) Fine, Glycogen synthase kinase-3 inhibition induces glioma cell death through c-MYC, nuclear factor-kappa B, and glucose regulation. Cancer Res 68:6643–6651CrossRefPubMedPubMedCentral Kotliarova S, Pastorino S, Kovell LC et al (2008) Fine, Glycogen synthase kinase-3 inhibition induces glioma cell death through c-MYC, nuclear factor-kappa B, and glucose regulation. Cancer Res 68:6643–6651CrossRefPubMedPubMedCentral
9.
go back to reference Glunde K, Penet MF, Jiang L et al (2005) Choline metabolism-based molecular diagnosis of cancer: an update. Expert Rev Mol Diagn 15:735–747CrossRef Glunde K, Penet MF, Jiang L et al (2005) Choline metabolism-based molecular diagnosis of cancer: an update. Expert Rev Mol Diagn 15:735–747CrossRef
10.
go back to reference Podo F, Saradanelli E, Iorio R et al (2007) Abnormal choline phospholipid metabolism in breast and ovary cancer: molecular bases for noninvasive imaging approaches. Curr Med Imaging Rev 3:123–137CrossRef Podo F, Saradanelli E, Iorio R et al (2007) Abnormal choline phospholipid metabolism in breast and ovary cancer: molecular bases for noninvasive imaging approaches. Curr Med Imaging Rev 3:123–137CrossRef
11.
go back to reference Smith TAD, Glaholm J, Leach MO et al (1991) A comparison of in vivo and in vitro 31P NMR spectra from human breast tumours: variations in phosphorus metabolism. Br J Cancer 63:514–516CrossRefPubMedPubMedCentral Smith TAD, Glaholm J, Leach MO et al (1991) A comparison of in vivo and in vitro 31P NMR spectra from human breast tumours: variations in phosphorus metabolism. Br J Cancer 63:514–516CrossRefPubMedPubMedCentral
12.
go back to reference Leach MO, Verrill M, Glaholm J et al (1998) Measurements of Human Breast Cancer using Magnetic Resonance Spectroscopy: a review of clinical measurement and a report of localized 31P measurements of response to treatment. NMR Biomed 11:314–340CrossRefPubMed Leach MO, Verrill M, Glaholm J et al (1998) Measurements of Human Breast Cancer using Magnetic Resonance Spectroscopy: a review of clinical measurement and a report of localized 31P measurements of response to treatment. NMR Biomed 11:314–340CrossRefPubMed
13.
go back to reference Kletzien RF, Perdue JF (1974) Sugar transport in chick embryo fibroblasts. J Biol Chem 249:3366–3374PubMed Kletzien RF, Perdue JF (1974) Sugar transport in chick embryo fibroblasts. J Biol Chem 249:3366–3374PubMed
15.
go back to reference Hosotani K, Kitagawa M (2003) Improved simultaneous determination method of b-carotene and retinol with saponification in human serum and rat liver. J Chromatogr B 791:305–313CrossRef Hosotani K, Kitagawa M (2003) Improved simultaneous determination method of b-carotene and retinol with saponification in human serum and rat liver. J Chromatogr B 791:305–313CrossRef
16.
go back to reference Tan HM, Aziz ARA, Aroua MK (2013) Glycerol production and its applications as a raw material: a review. Renew Sustain Energy Rev 27:118–127CrossRef Tan HM, Aziz ARA, Aroua MK (2013) Glycerol production and its applications as a raw material: a review. Renew Sustain Energy Rev 27:118–127CrossRef
17.
go back to reference Phyu SM, Tseng CC, Fleming IN, Smith TAD (2016) Probing the PI3K/Akt/mTor pathway using 31P-NMR spectroscopy: routes to glycogen synthase kinase 3. Sci Rep 6:36544CrossRefPubMedPubMedCentral Phyu SM, Tseng CC, Fleming IN, Smith TAD (2016) Probing the PI3K/Akt/mTor pathway using 31P-NMR spectroscopy: routes to glycogen synthase kinase 3. Sci Rep 6:36544CrossRefPubMedPubMedCentral
18.
go back to reference Carrasco S, Merida I (2007) Diacylglycerol, when simplicity becomes complex. Trends Biochem Sci 32:27–36CrossRefPubMed Carrasco S, Merida I (2007) Diacylglycerol, when simplicity becomes complex. Trends Biochem Sci 32:27–36CrossRefPubMed
19.
go back to reference Ridgway ND (2013) The role of phosphatidylcholine and choline metabolites to cell proliferation and survival. Crit Rev Biochem Mol Biol 48:20–38CrossRefPubMed Ridgway ND (2013) The role of phosphatidylcholine and choline metabolites to cell proliferation and survival. Crit Rev Biochem Mol Biol 48:20–38CrossRefPubMed
21.
go back to reference Ide Y, Waki M, Hayasaka T et al (2013) Human breast cancer tissues contain abundant phosphatidylcholine(36:1) with high stearoyl-CoA desaturase-1 expression. PLoS One 8:e61204CrossRefPubMedPubMedCentral Ide Y, Waki M, Hayasaka T et al (2013) Human breast cancer tissues contain abundant phosphatidylcholine(36:1) with high stearoyl-CoA desaturase-1 expression. PLoS One 8:e61204CrossRefPubMedPubMedCentral
22.
go back to reference Sovadinova I, Babica P, Boeke H et al (2015) Phosphatidylcholine specific PLC-induced dysregulation of gap junctions, a robust cellular response to environmental toxicants, and prevention by resveratrol in a rat liver cell model. PLoS One 10:e0124454CrossRefPubMedPubMedCentral Sovadinova I, Babica P, Boeke H et al (2015) Phosphatidylcholine specific PLC-induced dysregulation of gap junctions, a robust cellular response to environmental toxicants, and prevention by resveratrol in a rat liver cell model. PLoS One 10:e0124454CrossRefPubMedPubMedCentral
23.
24.
go back to reference Trnski D, Sabol M, Gojevic A et al (2015) GSK3 beta and Gli3 play a role in activation of Hedgehog-Gli pathway in human colon cancer—targeting GSK3 beta downregulates the signaling pathway and reduces cell proliferation. Biochim Biophys Acta Mol Basis Dis 1852:2574–2584CrossRef Trnski D, Sabol M, Gojevic A et al (2015) GSK3 beta and Gli3 play a role in activation of Hedgehog-Gli pathway in human colon cancer—targeting GSK3 beta downregulates the signaling pathway and reduces cell proliferation. Biochim Biophys Acta Mol Basis Dis 1852:2574–2584CrossRef
25.
go back to reference Zeng J, Liu D, Qiu ZX et al (2014) GSK3 beta overexpression indicates poor prognosis and its inhibition reduces cell proliferation and survival of non-small cell lung cancer. PLoS One 9:e91231CrossRefPubMedPubMedCentral Zeng J, Liu D, Qiu ZX et al (2014) GSK3 beta overexpression indicates poor prognosis and its inhibition reduces cell proliferation and survival of non-small cell lung cancer. PLoS One 9:e91231CrossRefPubMedPubMedCentral
26.
go back to reference Kim HM, Kim CS, Lee JH et al (2013) CG0009, a novel glycogen synthase kinase 3 inhibitor, induces cell death through cyclin d1 depletion in breast cancer cells. PLoS One 8:e60383CellsCrossRef Kim HM, Kim CS, Lee JH et al (2013) CG0009, a novel glycogen synthase kinase 3 inhibitor, induces cell death through cyclin d1 depletion in breast cancer cells. PLoS One 8:e60383CellsCrossRef
27.
go back to reference Ha DT, Trinh NT, Hien TT et al (2010) Selected compounds derived from Moutan Cortex stimulated glucose uptake and glycogen synthesis via AMPK activation in human HepG2 cells. J Ethnopharmacol 131:417–424CrossRef Ha DT, Trinh NT, Hien TT et al (2010) Selected compounds derived from Moutan Cortex stimulated glucose uptake and glycogen synthesis via AMPK activation in human HepG2 cells. J Ethnopharmacol 131:417–424CrossRef
28.
go back to reference Park GB, Chung YH, Gong JH et al (2016) GSK-3 beta-mediated fatty acid synthesis enhances epithelial to mesenchymal transition of TLR4-activated colorectal cancer cells through regulation of TAp63. Int J Oncol 49:2163–2172CrossRefPubMed Park GB, Chung YH, Gong JH et al (2016) GSK-3 beta-mediated fatty acid synthesis enhances epithelial to mesenchymal transition of TLR4-activated colorectal cancer cells through regulation of TAp63. Int J Oncol 49:2163–2172CrossRefPubMed
29.
go back to reference Al-saffar NMS, Jackson E, Raynaud FI et al (2010) The phosphoinositide 3-kinase inhibitor PI-103 downregulates choline kinase a leading to phosphocholine and total choline decrease detected by magnetic resonance spectroscopy. Cancer Res 70:5507–5517CrossRefPubMedPubMedCentral Al-saffar NMS, Jackson E, Raynaud FI et al (2010) The phosphoinositide 3-kinase inhibitor PI-103 downregulates choline kinase a leading to phosphocholine and total choline decrease detected by magnetic resonance spectroscopy. Cancer Res 70:5507–5517CrossRefPubMedPubMedCentral
30.
go back to reference Anthony ML, Zhao M, Brindle KM (1999) Inhibition of phosphatidylcholine biosynthesis following induction of apoptosis in HL-60 cells. J Biol Chem 274:19686–19692CrossRefPubMed Anthony ML, Zhao M, Brindle KM (1999) Inhibition of phosphatidylcholine biosynthesis following induction of apoptosis in HL-60 cells. J Biol Chem 274:19686–19692CrossRefPubMed
31.
go back to reference Al-Saeedi F, Welch AE, Smith TAD (2005) [methyl-3H] choline incorporation into MCF7 tumour cells: correlation with proliferation. Eur J Nucl Med 32:660–667CrossRef Al-Saeedi F, Welch AE, Smith TAD (2005) [methyl-3H] choline incorporation into MCF7 tumour cells: correlation with proliferation. Eur J Nucl Med 32:660–667CrossRef
32.
go back to reference Lagemaat MW, Maas MC, Vos EK et al (2015) 31P MR spectroscopic imaging of the human prostate at 7T:T1 relaxation times, nuclear overhauser effect, and spectral characterization. Magn Resonan Med 73:909–920CrossRef Lagemaat MW, Maas MC, Vos EK et al (2015) 31P MR spectroscopic imaging of the human prostate at 7T:T1 relaxation times, nuclear overhauser effect, and spectral characterization. Magn Resonan Med 73:909–920CrossRef
Metadata
Title
CDP-choline accumulation in breast and colorectal cancer cells treated with a GSK-3-targeting inhibitor
Authors
Su Myat Phyu
Chih-Chung Tseng
Tim Andrew Davies Smith
Publication date
01-04-2019
Publisher
Springer International Publishing
Published in
Magnetic Resonance Materials in Physics, Biology and Medicine / Issue 2/2019
Print ISSN: 0968-5243
Electronic ISSN: 1352-8661
DOI
https://doi.org/10.1007/s10334-018-0719-3

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