The Experts below are selected from a list of 1200 Experts worldwide ranked by ideXlab platform
Arend Heerschap - One of the best experts on this subject based on the ideXlab platform.
-
idh1 r132h mutation generates a distinct Phospholipid Metabolite profile in glioma
Cancer Research, 2014Co-Authors: Morteza Esmaeili, Bob C Hamans, Anna C Navis, Remco Van Horssen, Tone Frost Bathen, Ingrid S Gribbestad, William P J Leenders, Arend HeerschapAbstract:Many patients with glioma harbor specific mutations in the isocitrate dehydrogenase gene IDH1 that associate with a relatively better prognosis. IDH1-mutated tumors produce the oncoMetabolite 2-hydroxyglutarate. Because IDH1 also regulates several pathways leading to lipid synthesis, we hypothesized that IDH1-mutant tumors have an altered Phospholipid Metabolite profile that would impinge on tumor pathobiology. To investigate this hypothesis, we performed (31)P-MRS imaging in mouse xenograft models of four human gliomas, one of which harbored the IDH1-R132H mutation. (31)P-MR spectra from the IDH1-mutant tumor displayed a pattern distinct from that of the three IDH1 wild-type tumors, characterized by decreased levels of phosphoethanolamine and increased levels of glycerophosphocholine. This spectral profile was confirmed by ex vivo analysis of tumor extracts, and it was also observed in human surgical biopsies of IDH1-mutated tumors by (31)P high-resolution magic angle spinning spectroscopy. The specificity of this profile for the IDH1-R132H mutation was established by in vitro (31)P-NMR of extracts of cells overexpressing IDH1 or IDH1-R132H. Overall, our results provide evidence that the IDH1-R132H mutation alters Phospholipid metabolism in gliomas involving phosphoethanolamine and glycerophosphocholine. These new noninvasive biomarkers can assist in the identification of the mutation and in research toward novel treatments that target aberrant metabolism in IDH1-mutant glioma.
-
IDH1 R132H Mutation Generates a Distinct Phospholipid Metabolite Profile in Glioma
Cancer Research, 2014Co-Authors: Morteza Esmaeili, Bob C Hamans, Anna C Navis, Remco Van Horssen, Tone Frost Bathen, Ingrid S Gribbestad, William P J Leenders, Arend HeerschapAbstract:This study reports novel noninvasive biomarkers of IDH-mutant gliomas that may help to guide treatments to target aberrant metabolism in these aggressive brain tumors.
-
In Vivo 31P magnetic resonance spectroscopic imaging (MRSI) for metabolic profiling of human breast cancer xenografts
Journal of Magnetic Resonance Imaging, 2014Co-Authors: Morteza Esmaeili, Bob C Hamans, Tone Frost Bathen, Ingrid S Gribbestad, Siver Andreas Moestue, Andor Veltien, Alexandr Kristian, Olav Engebråten, Gunhild Mari Mælandsmo, Arend HeerschapAbstract:To study cancer associated with abnormal metabolism of Phospholipids, of which several have been proposed as biomarkers for malignancy or to monitor response to anticancer therapy. We explored 3D (31) P magnetic resonance spectroscopic imaging (MRSI) at high magnetic field for in vivo assessment of individual Phospholipids in two patient-derived breast cancer xenografts representing good and poor prognosis (luminal- and basal-like tumors).Metabolic profiles from luminal-like and basal-like xenograft tumors were obtained in vivo using 3D (31) P MRSI at 11.7T and from tissue extracts in vitro at 14.1T. Gene expression analysis was performed in order to support metabolic differences between the two xenografts.In vivo (31) P MR spectra were obtained in which the prominent resonances from Phospholipid Metabolites were detected at a high signal-to-noise ratio (SNR >7.5). Metabolic profiles obtained in vivo were in agreement with those obtained in vitro and could be used to discriminate between the two xenograft models, based on the levels of phosphocholine, phosphoethanolamine, glycerophosphocholine, and glycerophosphoethanolamine. The differences in Phospholipid Metabolite concentration could partly be explained by gene expression profiles.Noninvasive metabolic profiling by 3D (31) P MRSI can discriminate between subtypes of breast cancer based on different concentrations of choline- and ethanolamine-containing Phospholipids.J. Magn. Reson. Imaging 2014. © 2014 Wiley Periodicals, Inc.
Zaver M. Bhujwalla - One of the best experts on this subject based on the ideXlab platform.
-
silencing of the glycerophosphocholine phosphodiesterase gdpd5 alters the Phospholipid Metabolite profile in a breast cancer model in vivo as monitored by 31p magnetic resonance spectroscopy
NMR in Biomedicine, 2014Co-Authors: Jannie P. Wijnen, Maria D. Cao, Mailin Döpkens, Balaji Krishnamachary, Zaver M. Bhujwalla, Tiffany R. Greenwood, Lu Jiang, Menglin Cheng, Dennis W.j. Klomp, Kristine GlundeAbstract:Abnormal choline Phospholipid metabolism is an emerging hallmark of cancer, which is implicated in carcinogenesis and tumor progression. The malignant metabolic phenotype is characterized by high levels of phosphocholine (PC) and relatively low levels of glycerophosphocholine (GPC) in aggressive breast cancer cells. Phosphorus Magnetic Resonance Spectroscopy (31P MRS) is able to noninvasively detect these water-soluble Metabolites of choline as well as ethanolamine Phospholipid metabolism. Here we have investigated the effects of stably silencing glycerophosphoester diesterase domain containing 5 (GDPD5), which is an enzyme with glycerophosphocholine phosphodiesterase activity, in MDA-MB-231 breast cancer cells and orthotopic tumor xenografts. Tumors in which GDPD5 was stably silenced with GDPD5-specific shRNA contained increased levels of GPC and phosphoethanolamine (PE) compared to control tumors.
-
Silencing of the glycerophosphocholine phosphodiesterase GDPD5 alters the Phospholipid Metabolite profile in a breast cancer model in vivo as monitored by 31P MRS
NMR in Biomedicine, 2014Co-Authors: Jannie P. Wijnen, Maria D. Cao, Mailin Döpkens, Balaji Krishnamachary, Zaver M. Bhujwalla, Tiffany R. Greenwood, Lu Jiang, Menglin Cheng, Dennis W.j. Klomp, Kristine GlundeAbstract:Abnormal choline Phospholipid metabolism is an emerging hallmark of cancer, which is implicated in carcinogenesis and tumor progression. The malignant metabolic phenotype is characterized by high levels of phosphocholine (PC) and relatively low levels of glycerophosphocholine (GPC) in aggressive breast cancer cells. Phosphorus (31P) MRS is able to non-invasively detect these water-soluble Metabolites of choline as well as ethanolamine Phospholipid metabolism. Here we have investigated the effects of stably silencing glycerophosphoester diesterase domain containing 5 (GDPD5), which is an enzyme with glycerophosphocholine phosphodiesterase activity, in MDA-MB-231 breast cancer cells and orthotopic tumor xenografts. Tumors in which GDPD5 was stably silenced with GDPD5-specific shRNA contained increased levels of GPC and phosphoethanolamine (PE) compared with control tumors. Copyright © 2014 John Wiley & Sons, Ltd.
-
glycerophosphodiester phosphodiesterase domain containing 5 gdpd5 expression correlates with malignant choline Phospholipid Metabolite profiles in human breast cancer
NMR in Biomedicine, 2012Co-Authors: Maria D. Cao, Mailin Döpkens, Balaji Krishnamachary, Farhad Vesuna, Mayur Gadiya, Per Eystein Lønning, Zaver M. BhujwallaAbstract:Altered choline Phospholipid metabolism is a hallmark of cancer, leading to malignant choline Metabolite profiles consisting of low glycerophosphocholine (GPC) and high phosphocholine (PC) in human breast cancers. Glycerophosphocholine phosphodiesterase (GPC-PDE) catalyzes the degradation of GPC to free choline and glycerol-3-phosphate. The gene(s) encoding for the GPC-PDE(s) responsible for GPC degradation in breast cancers have not yet been identified. Here, we demonstrate for the first time that the GPC-PDE encoded by glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5) is associated with breast cancer malignancy. Two human breast cancer cell lines (n=8 and n=10) and primary human breast tumor samples (n=19) were studied with combined MRS and quantitative reverse transcription-polymerase chain reaction to investigate several isoforms of GDPD expression with respect to choline Phospholipid Metabolite levels. Of the five GDPDs tested, GDPD5 was found to be significantly overexpressed in highly malignant estrogen receptor negative (ER – ) compared with weakly malignant estrogen receptor positive (ER + ) human breast cancer cells (p=0.027) and breast tumors from patients (p=0.015). GDPD5 showed significantly positive correlations with PC (p<0.001), total choline (tCho) (p=0.007) and PC/GPC (p<0.001) levels in human breast tumors. GDPD5showedatrendtowardsanegativecorrelationwithGPClevels(p=0.130).Humanbreastcancerswithmalignant choline Metabolite profiles consisting of low GPC and high PC levels highly co-expressed GDPD5, choline kinase alpha (CHKA)and phosphatidylcholine-specific phospholipaseD1 (PLD1),whereas cancerscontaininghighGPC and relatively low PC levels displayed low co-expression of GDPD5, CHKA and PLD1. GDPD5, CHKA and PLD1 were significantly overexpressed in highly malignant ER – tumors in our patient cohort. Our study identified GDPD5 as a GPC-PDE that probably participates in the regulation of choline Phospholipid metabolism in breast cancer, which possibly occurs in cooperation with CHKA and PLD1. Copyright © 2012 John Wiley & Sons, Ltd.
-
Glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5) expression correlates with malignant choline Phospholipid Metabolite profiles in human breast cancer.
NMR in Biomedicine, 2012Co-Authors: Maria D. Cao, Ingrid S Gribbestad, Mailin Döpkens, Balaji Krishnamachary, Farhad Vesuna, Mayur Gadiya, Per Eystein Lønning, Zaver M. Bhujwalla, Kristine GlundeAbstract:Altered choline Phospholipid metabolism is a hallmark of cancer, leading to malignant choline Metabolite profiles consisting of low glycerophosphocholine (GPC) and high phosphocholine (PC) in human breast cancers. Glycerophosphocholine phosphodiesterase (GPC-PDE) catalyzes the degradation of GPC to free choline and glycerol-3-phosphate. The gene(s) encoding for the GPC-PDE(s) responsible for GPC degradation in breast cancers have not yet been identified. Here, we demonstrate for the first time that the GPC-PDE encoded by glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5) is associated with breast cancer malignancy. Two human breast cancer cell lines (n=8 and n=10) and primary human breast tumor samples (n=19) were studied with combined MRS and quantitative reverse transcription-polymerase chain reaction to investigate several isoforms of GDPD expression with respect to choline Phospholipid Metabolite levels. Of the five GDPDs tested, GDPD5 was found to be significantly overexpressed in highly malignant estrogen receptor negative (ER – ) compared with weakly malignant estrogen receptor positive (ER + ) human breast cancer cells (p=0.027) and breast tumors from patients (p=0.015). GDPD5 showed significantly positive correlations with PC (p
-
Loss of p53 function in colon cancer cells results in increased phosphocholine and total choline.
Molecular Imaging, 2004Co-Authors: Noriko Mori, Zaver M. Bhujwalla, Robert Delsite, Kshama Natarajan, Mariola Kulawiec, Keshav K. SinghAbstract:Mutations in the p53 gene are the most frequently observed genetic lesions in human cancers. Human cancers that contain a p53 mutation are more aggressive, more apt to metastasize, and more often fatal. p53 controls numerous downstream targets that can influence various outcomes such as apoptosis, growth arrest, and DNA repair. Based on previous observations using (1)H magnetic resonance spectroscopy (MRS), we have identified choline Phospholipid Metabolite intensities typical of increased malignancy. Here we have used (1)H MRS to characterize the choline Phospholipid Metabolite levels of p53(+/ +) and p53(-/-) cells, and demonstrated that loss of p53 function results in increased phosphocholine and total choline. These data suggest that the increased malignancy of cancer cells resulting from loss of p53 may be mediated, in part, through the choline Phospholipid pathway.
Maria D. Cao - One of the best experts on this subject based on the ideXlab platform.
-
silencing of the glycerophosphocholine phosphodiesterase gdpd5 alters the Phospholipid Metabolite profile in a breast cancer model in vivo as monitored by 31p magnetic resonance spectroscopy
NMR in Biomedicine, 2014Co-Authors: Jannie P. Wijnen, Maria D. Cao, Mailin Döpkens, Balaji Krishnamachary, Zaver M. Bhujwalla, Tiffany R. Greenwood, Lu Jiang, Menglin Cheng, Dennis W.j. Klomp, Kristine GlundeAbstract:Abnormal choline Phospholipid metabolism is an emerging hallmark of cancer, which is implicated in carcinogenesis and tumor progression. The malignant metabolic phenotype is characterized by high levels of phosphocholine (PC) and relatively low levels of glycerophosphocholine (GPC) in aggressive breast cancer cells. Phosphorus Magnetic Resonance Spectroscopy (31P MRS) is able to noninvasively detect these water-soluble Metabolites of choline as well as ethanolamine Phospholipid metabolism. Here we have investigated the effects of stably silencing glycerophosphoester diesterase domain containing 5 (GDPD5), which is an enzyme with glycerophosphocholine phosphodiesterase activity, in MDA-MB-231 breast cancer cells and orthotopic tumor xenografts. Tumors in which GDPD5 was stably silenced with GDPD5-specific shRNA contained increased levels of GPC and phosphoethanolamine (PE) compared to control tumors.
-
Silencing of the glycerophosphocholine phosphodiesterase GDPD5 alters the Phospholipid Metabolite profile in a breast cancer model in vivo as monitored by 31P MRS
NMR in Biomedicine, 2014Co-Authors: Jannie P. Wijnen, Maria D. Cao, Mailin Döpkens, Balaji Krishnamachary, Zaver M. Bhujwalla, Tiffany R. Greenwood, Lu Jiang, Menglin Cheng, Dennis W.j. Klomp, Kristine GlundeAbstract:Abnormal choline Phospholipid metabolism is an emerging hallmark of cancer, which is implicated in carcinogenesis and tumor progression. The malignant metabolic phenotype is characterized by high levels of phosphocholine (PC) and relatively low levels of glycerophosphocholine (GPC) in aggressive breast cancer cells. Phosphorus (31P) MRS is able to non-invasively detect these water-soluble Metabolites of choline as well as ethanolamine Phospholipid metabolism. Here we have investigated the effects of stably silencing glycerophosphoester diesterase domain containing 5 (GDPD5), which is an enzyme with glycerophosphocholine phosphodiesterase activity, in MDA-MB-231 breast cancer cells and orthotopic tumor xenografts. Tumors in which GDPD5 was stably silenced with GDPD5-specific shRNA contained increased levels of GPC and phosphoethanolamine (PE) compared with control tumors. Copyright © 2014 John Wiley & Sons, Ltd.
-
glycerophosphodiester phosphodiesterase domain containing 5 gdpd5 expression correlates with malignant choline Phospholipid Metabolite profiles in human breast cancer
NMR in Biomedicine, 2012Co-Authors: Maria D. Cao, Mailin Döpkens, Balaji Krishnamachary, Farhad Vesuna, Mayur Gadiya, Per Eystein Lønning, Zaver M. BhujwallaAbstract:Altered choline Phospholipid metabolism is a hallmark of cancer, leading to malignant choline Metabolite profiles consisting of low glycerophosphocholine (GPC) and high phosphocholine (PC) in human breast cancers. Glycerophosphocholine phosphodiesterase (GPC-PDE) catalyzes the degradation of GPC to free choline and glycerol-3-phosphate. The gene(s) encoding for the GPC-PDE(s) responsible for GPC degradation in breast cancers have not yet been identified. Here, we demonstrate for the first time that the GPC-PDE encoded by glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5) is associated with breast cancer malignancy. Two human breast cancer cell lines (n=8 and n=10) and primary human breast tumor samples (n=19) were studied with combined MRS and quantitative reverse transcription-polymerase chain reaction to investigate several isoforms of GDPD expression with respect to choline Phospholipid Metabolite levels. Of the five GDPDs tested, GDPD5 was found to be significantly overexpressed in highly malignant estrogen receptor negative (ER – ) compared with weakly malignant estrogen receptor positive (ER + ) human breast cancer cells (p=0.027) and breast tumors from patients (p=0.015). GDPD5 showed significantly positive correlations with PC (p<0.001), total choline (tCho) (p=0.007) and PC/GPC (p<0.001) levels in human breast tumors. GDPD5showedatrendtowardsanegativecorrelationwithGPClevels(p=0.130).Humanbreastcancerswithmalignant choline Metabolite profiles consisting of low GPC and high PC levels highly co-expressed GDPD5, choline kinase alpha (CHKA)and phosphatidylcholine-specific phospholipaseD1 (PLD1),whereas cancerscontaininghighGPC and relatively low PC levels displayed low co-expression of GDPD5, CHKA and PLD1. GDPD5, CHKA and PLD1 were significantly overexpressed in highly malignant ER – tumors in our patient cohort. Our study identified GDPD5 as a GPC-PDE that probably participates in the regulation of choline Phospholipid metabolism in breast cancer, which possibly occurs in cooperation with CHKA and PLD1. Copyright © 2012 John Wiley & Sons, Ltd.
-
Glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5) expression correlates with malignant choline Phospholipid Metabolite profiles in human breast cancer.
NMR in Biomedicine, 2012Co-Authors: Maria D. Cao, Ingrid S Gribbestad, Mailin Döpkens, Balaji Krishnamachary, Farhad Vesuna, Mayur Gadiya, Per Eystein Lønning, Zaver M. Bhujwalla, Kristine GlundeAbstract:Altered choline Phospholipid metabolism is a hallmark of cancer, leading to malignant choline Metabolite profiles consisting of low glycerophosphocholine (GPC) and high phosphocholine (PC) in human breast cancers. Glycerophosphocholine phosphodiesterase (GPC-PDE) catalyzes the degradation of GPC to free choline and glycerol-3-phosphate. The gene(s) encoding for the GPC-PDE(s) responsible for GPC degradation in breast cancers have not yet been identified. Here, we demonstrate for the first time that the GPC-PDE encoded by glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5) is associated with breast cancer malignancy. Two human breast cancer cell lines (n=8 and n=10) and primary human breast tumor samples (n=19) were studied with combined MRS and quantitative reverse transcription-polymerase chain reaction to investigate several isoforms of GDPD expression with respect to choline Phospholipid Metabolite levels. Of the five GDPDs tested, GDPD5 was found to be significantly overexpressed in highly malignant estrogen receptor negative (ER – ) compared with weakly malignant estrogen receptor positive (ER + ) human breast cancer cells (p=0.027) and breast tumors from patients (p=0.015). GDPD5 showed significantly positive correlations with PC (p
Morteza Esmaeili - One of the best experts on this subject based on the ideXlab platform.
-
idh1 r132h mutation generates a distinct Phospholipid Metabolite profile in glioma
Cancer Research, 2014Co-Authors: Morteza Esmaeili, Bob C Hamans, Anna C Navis, Remco Van Horssen, Tone Frost Bathen, Ingrid S Gribbestad, William P J Leenders, Arend HeerschapAbstract:Many patients with glioma harbor specific mutations in the isocitrate dehydrogenase gene IDH1 that associate with a relatively better prognosis. IDH1-mutated tumors produce the oncoMetabolite 2-hydroxyglutarate. Because IDH1 also regulates several pathways leading to lipid synthesis, we hypothesized that IDH1-mutant tumors have an altered Phospholipid Metabolite profile that would impinge on tumor pathobiology. To investigate this hypothesis, we performed (31)P-MRS imaging in mouse xenograft models of four human gliomas, one of which harbored the IDH1-R132H mutation. (31)P-MR spectra from the IDH1-mutant tumor displayed a pattern distinct from that of the three IDH1 wild-type tumors, characterized by decreased levels of phosphoethanolamine and increased levels of glycerophosphocholine. This spectral profile was confirmed by ex vivo analysis of tumor extracts, and it was also observed in human surgical biopsies of IDH1-mutated tumors by (31)P high-resolution magic angle spinning spectroscopy. The specificity of this profile for the IDH1-R132H mutation was established by in vitro (31)P-NMR of extracts of cells overexpressing IDH1 or IDH1-R132H. Overall, our results provide evidence that the IDH1-R132H mutation alters Phospholipid metabolism in gliomas involving phosphoethanolamine and glycerophosphocholine. These new noninvasive biomarkers can assist in the identification of the mutation and in research toward novel treatments that target aberrant metabolism in IDH1-mutant glioma.
-
IDH1 R132H Mutation Generates a Distinct Phospholipid Metabolite Profile in Glioma
Cancer Research, 2014Co-Authors: Morteza Esmaeili, Bob C Hamans, Anna C Navis, Remco Van Horssen, Tone Frost Bathen, Ingrid S Gribbestad, William P J Leenders, Arend HeerschapAbstract:This study reports novel noninvasive biomarkers of IDH-mutant gliomas that may help to guide treatments to target aberrant metabolism in these aggressive brain tumors.
-
In Vivo 31P magnetic resonance spectroscopic imaging (MRSI) for metabolic profiling of human breast cancer xenografts
Journal of Magnetic Resonance Imaging, 2014Co-Authors: Morteza Esmaeili, Bob C Hamans, Tone Frost Bathen, Ingrid S Gribbestad, Siver Andreas Moestue, Andor Veltien, Alexandr Kristian, Olav Engebråten, Gunhild Mari Mælandsmo, Arend HeerschapAbstract:To study cancer associated with abnormal metabolism of Phospholipids, of which several have been proposed as biomarkers for malignancy or to monitor response to anticancer therapy. We explored 3D (31) P magnetic resonance spectroscopic imaging (MRSI) at high magnetic field for in vivo assessment of individual Phospholipids in two patient-derived breast cancer xenografts representing good and poor prognosis (luminal- and basal-like tumors).Metabolic profiles from luminal-like and basal-like xenograft tumors were obtained in vivo using 3D (31) P MRSI at 11.7T and from tissue extracts in vitro at 14.1T. Gene expression analysis was performed in order to support metabolic differences between the two xenografts.In vivo (31) P MR spectra were obtained in which the prominent resonances from Phospholipid Metabolites were detected at a high signal-to-noise ratio (SNR >7.5). Metabolic profiles obtained in vivo were in agreement with those obtained in vitro and could be used to discriminate between the two xenograft models, based on the levels of phosphocholine, phosphoethanolamine, glycerophosphocholine, and glycerophosphoethanolamine. The differences in Phospholipid Metabolite concentration could partly be explained by gene expression profiles.Noninvasive metabolic profiling by 3D (31) P MRSI can discriminate between subtypes of breast cancer based on different concentrations of choline- and ethanolamine-containing Phospholipids.J. Magn. Reson. Imaging 2014. © 2014 Wiley Periodicals, Inc.
Kristine Glunde - One of the best experts on this subject based on the ideXlab platform.
-
silencing of the glycerophosphocholine phosphodiesterase gdpd5 alters the Phospholipid Metabolite profile in a breast cancer model in vivo as monitored by 31p magnetic resonance spectroscopy
NMR in Biomedicine, 2014Co-Authors: Jannie P. Wijnen, Maria D. Cao, Mailin Döpkens, Balaji Krishnamachary, Zaver M. Bhujwalla, Tiffany R. Greenwood, Lu Jiang, Menglin Cheng, Dennis W.j. Klomp, Kristine GlundeAbstract:Abnormal choline Phospholipid metabolism is an emerging hallmark of cancer, which is implicated in carcinogenesis and tumor progression. The malignant metabolic phenotype is characterized by high levels of phosphocholine (PC) and relatively low levels of glycerophosphocholine (GPC) in aggressive breast cancer cells. Phosphorus Magnetic Resonance Spectroscopy (31P MRS) is able to noninvasively detect these water-soluble Metabolites of choline as well as ethanolamine Phospholipid metabolism. Here we have investigated the effects of stably silencing glycerophosphoester diesterase domain containing 5 (GDPD5), which is an enzyme with glycerophosphocholine phosphodiesterase activity, in MDA-MB-231 breast cancer cells and orthotopic tumor xenografts. Tumors in which GDPD5 was stably silenced with GDPD5-specific shRNA contained increased levels of GPC and phosphoethanolamine (PE) compared to control tumors.
-
Silencing of the glycerophosphocholine phosphodiesterase GDPD5 alters the Phospholipid Metabolite profile in a breast cancer model in vivo as monitored by 31P MRS
NMR in Biomedicine, 2014Co-Authors: Jannie P. Wijnen, Maria D. Cao, Mailin Döpkens, Balaji Krishnamachary, Zaver M. Bhujwalla, Tiffany R. Greenwood, Lu Jiang, Menglin Cheng, Dennis W.j. Klomp, Kristine GlundeAbstract:Abnormal choline Phospholipid metabolism is an emerging hallmark of cancer, which is implicated in carcinogenesis and tumor progression. The malignant metabolic phenotype is characterized by high levels of phosphocholine (PC) and relatively low levels of glycerophosphocholine (GPC) in aggressive breast cancer cells. Phosphorus (31P) MRS is able to non-invasively detect these water-soluble Metabolites of choline as well as ethanolamine Phospholipid metabolism. Here we have investigated the effects of stably silencing glycerophosphoester diesterase domain containing 5 (GDPD5), which is an enzyme with glycerophosphocholine phosphodiesterase activity, in MDA-MB-231 breast cancer cells and orthotopic tumor xenografts. Tumors in which GDPD5 was stably silenced with GDPD5-specific shRNA contained increased levels of GPC and phosphoethanolamine (PE) compared with control tumors. Copyright © 2014 John Wiley & Sons, Ltd.
-
Glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5) expression correlates with malignant choline Phospholipid Metabolite profiles in human breast cancer.
NMR in Biomedicine, 2012Co-Authors: Maria D. Cao, Ingrid S Gribbestad, Mailin Döpkens, Balaji Krishnamachary, Farhad Vesuna, Mayur Gadiya, Per Eystein Lønning, Zaver M. Bhujwalla, Kristine GlundeAbstract:Altered choline Phospholipid metabolism is a hallmark of cancer, leading to malignant choline Metabolite profiles consisting of low glycerophosphocholine (GPC) and high phosphocholine (PC) in human breast cancers. Glycerophosphocholine phosphodiesterase (GPC-PDE) catalyzes the degradation of GPC to free choline and glycerol-3-phosphate. The gene(s) encoding for the GPC-PDE(s) responsible for GPC degradation in breast cancers have not yet been identified. Here, we demonstrate for the first time that the GPC-PDE encoded by glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5) is associated with breast cancer malignancy. Two human breast cancer cell lines (n=8 and n=10) and primary human breast tumor samples (n=19) were studied with combined MRS and quantitative reverse transcription-polymerase chain reaction to investigate several isoforms of GDPD expression with respect to choline Phospholipid Metabolite levels. Of the five GDPDs tested, GDPD5 was found to be significantly overexpressed in highly malignant estrogen receptor negative (ER – ) compared with weakly malignant estrogen receptor positive (ER + ) human breast cancer cells (p=0.027) and breast tumors from patients (p=0.015). GDPD5 showed significantly positive correlations with PC (p
-
GDPD5 inhibition alters the choline Phospholipid Metabolite profile of breast cancer cells toward a less malignant metabolic profile
Biomedical Spectroscopy and Imaging, 2012Co-Authors: Mailin Döpkens, Farhad Vesuna, Tiffany R. Greenwood, Venu Raman, Dieter Leibfritz, Kristine GlundeAbstract:Abstract. Altered choline Phospholipid metabolism is a metabolic hallmark of cancer. Malignant transformation of breast can-cer cells results in a switch from high glycerophosphocholine (GPC) and low phosphocholine (PC) to low GPC and high PC.Glycerophosphocholine phosphodiesterase (GPC-PDE; E.C. 3.1.4.2) catalyzes the degradation of GPC to choline (Cho) andglycerol-3-phosphate. The GPC-PDE gene(s) responsible for the relatively low GPC concentration in breast cancer cells havenot yet been characterized. Glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5) displays GPC-PDE ac-tivity, and is rapidly inhibited by sodium chloride and urea (NaCl/urea). We chemically inhibited GPC-PDE with NaCl/ureain nonmalignant MCF-12A breast epithelial cells, as well as in MCF-7 and MDA-MB-231 breast cancer cells. 1 H magneticresonance spectroscopy (MRS) of cell extracts demonstrated that exposure of MCF-12A, MCF-7 and MDA-MB-231 cells toNaCl/urea ( n = 5) significantly increased GPC and decreased PC, resulting in a low [PC]