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Article ; Online: Metabolic partitioning in the brain and its hijacking by glioblastoma.

de Ruiter Swain, Jed / Michalopoulou, Evdokia / Noch, Evan K / Lukey, Michael J / Van Aelst, Linda

2023 Volume 37, Issue 15-16, Page(s) 681–702

Abstract: The different cell types in the brain have highly specialized roles with unique metabolic requirements. Normal brain function requires the coordinated partitioning of metabolic pathways between these cells, such as in the neuron-astrocyte glutamate- ... ...

Abstract	The different cell types in the brain have highly specialized roles with unique metabolic requirements. Normal brain function requires the coordinated partitioning of metabolic pathways between these cells, such as in the neuron-astrocyte glutamate-glutamine cycle. An emerging theme in glioblastoma (GBM) biology is that malignant cells integrate into or "hijack" brain metabolism, co-opting neurons and glia for the supply of nutrients and recycling of waste products. Moreover, GBM cells communicate via signaling metabolites in the tumor microenvironment to promote tumor growth and induce immune suppression. Recent findings in this field point toward new therapeutic strategies to target the metabolic exchange processes that fuel tumorigenesis and suppress the anticancer immune response in GBM. Here, we provide an overview of the intercellular division of metabolic labor that occurs in both the normal brain and the GBM tumor microenvironment and then discuss the implications of these interactions for GBM therapy.
MeSH term(s)	Humans ; Glioblastoma ; Brain ; Neuroglia ; Astrocytes ; Neurons ; Tumor Microenvironment
Language	English
Publishing date	2023-08-30
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	806684-x
ISSN	1549-5477 ; 0890-9369
ISSN (online)	1549-5477
ISSN	0890-9369
DOI	10.1101/gad.350693.123
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Article ; Online: Chronic stress increases metastasis via neutrophil-mediated changes to the microenvironment.

Cancer cell

2024 Volume 42, Issue 3, Page(s) 474–486.e12

Abstract: Chronic stress is associated with increased risk of metastasis and poor survival in cancer patients, yet the reasons are unclear. We show that chronic stress increases lung metastasis from disseminated cancer cells 2- to 4-fold in mice. Chronic stress ... ...

Abstract	Chronic stress is associated with increased risk of metastasis and poor survival in cancer patients, yet the reasons are unclear. We show that chronic stress increases lung metastasis from disseminated cancer cells 2- to 4-fold in mice. Chronic stress significantly alters the lung microenvironment, with fibronectin accumulation, reduced T cell infiltration, and increased neutrophil infiltration. Depleting neutrophils abolishes stress-induced metastasis. Chronic stress shifts normal circadian rhythm of neutrophils and causes increased neutrophil extracellular trap (NET) formation via glucocorticoid release. In mice with neutrophil-specific glucocorticoid receptor deletion, chronic stress fails to increase NETs and metastasis. Furthermore, digesting NETs with DNase I prevents chronic stress-induced metastasis. Together, our data show that glucocorticoids released during chronic stress cause NET formation and establish a metastasis-promoting microenvironment. Therefore, NETs could be targets for preventing metastatic recurrence in cancer patients, many of whom will experience chronic stress due to their disease.
MeSH term(s)	Humans ; Animals ; Mice ; Neutrophils/pathology ; Extracellular Traps ; Lung Neoplasms/pathology ; Lung/pathology ; Tumor Microenvironment
Language	English
Publishing date	2024-02-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	2078448-X
ISSN	1878-3686 ; 1535-6108
ISSN (online)	1878-3686
ISSN	1535-6108
DOI	10.1016/j.ccell.2024.01.013
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Zs.A 5650: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Metabolic scavenging by cancer cells: when the going gets tough, the tough keep eating.

Michalopoulou, Evdokia / Bulusu, Vinay / Kamphorst, Jurre J

British journal of cancer

2016 Volume 115, Issue 6, Page(s) 635–640

Abstract: Cancer is fundamentally a disease of uncontrolled cell proliferation. Tumour metabolism has emerged as an exciting new discipline studying how cancer cells obtain the necessary energy and cellular 'building blocks' to sustain growth. Glucose and ... ...

Abstract	Cancer is fundamentally a disease of uncontrolled cell proliferation. Tumour metabolism has emerged as an exciting new discipline studying how cancer cells obtain the necessary energy and cellular 'building blocks' to sustain growth. Glucose and glutamine have long been regarded as the key nutrients fuelling tumour growth. However, the inhospitable tumour microenvironment of certain cancers, like pancreatic cancer, causes the supply of these nutrients to be chronically insufficient for the demands of proliferating cancer cells. Recent work has shown that cancer cells are able to overcome this nutrient insufficiency by scavenging alternative substrates, particularly proteins and lipids. Here, we review recent work identifying the endocytic process of macropinocytosis and subsequent lysosomal processing as an important substrate-acquisition route. In addition, we discuss the impact of hypoxia on fatty acid metabolism and the relevance of exogenous lipids for supporting tumour growth as well as the routes by which tumour cells can access these lipids. Together, these cancer-specific scavenging pathways provide a promising opportunity for therapeutic intervention.
MeSH term(s)	Animals ; Autophagy ; Cell Division ; Cell Hypoxia ; Energy Metabolism ; Fatty Acids/metabolism ; Humans ; Lipid Metabolism ; Macromolecular Substances/metabolism ; Metabolomics ; Neoplasm Proteins/metabolism ; Neoplasm Proteins/physiology ; Neoplasms/metabolism ; Neoplasms/pathology ; Pancreatic Neoplasms/metabolism ; Pancreatic Neoplasms/pathology ; Phosphatidylinositol 3-Kinases/physiology ; Pinocytosis/physiology ; Proto-Oncogene Proteins c-akt/physiology ; Signal Transduction/physiology ; TOR Serine-Threonine Kinases/physiology
Chemical Substances	Fatty Acids ; Macromolecular Substances ; Neoplasm Proteins ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; TOR Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2016-08-18
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	80075-2
ISSN	1532-1827 ; 0007-0920
ISSN (online)	1532-1827
ISSN	0007-0920
DOI	10.1038/bjc.2016.256
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Article ; Online: Triglycerides Promote Lipid Homeostasis during Hypoxic Stress by Balancing Fatty Acid Saturation.

Ackerman, Daniel / Tumanov, Sergey / Qiu, Bo / Michalopoulou, Evdokia / Spata, Michelle / Azzam, Andrew / Xie, Hong / Simon, M Celeste / Kamphorst, Jurre J

Cell reports

2018 Volume 24, Issue 10, Page(s) 2596–2605.e5

Abstract: Lipid droplets, which store triglycerides and cholesterol esters, are a prominent feature of clear cell renal cell carcinoma (ccRCC). Although their presence in ccRCC is critical for sustained tumorigenesis, their contribution to lipid homeostasis and ... ...

Abstract	Lipid droplets, which store triglycerides and cholesterol esters, are a prominent feature of clear cell renal cell carcinoma (ccRCC). Although their presence in ccRCC is critical for sustained tumorigenesis, their contribution to lipid homeostasis and tumor cell viability is incompletely understood. Here we show that disrupting triglyceride synthesis compromises the growth of both ccRCC tumors and ccRCC cells exposed to tumor-like conditions. Functionally, hypoxia leads to increased fatty acid saturation through inhibition of the oxygen-dependent stearoyl-CoA desaturase (SCD) enzyme. Triglycerides counter a toxic buildup of saturated lipids, primarily by releasing the unsaturated fatty acid oleate (the principal product of SCD activity) from lipid droplets into phospholipid pools. Disrupting this process derails lipid homeostasis, causing overproduction of toxic saturated ceramides and acyl-carnitines as well as activation of the NF-κB transcription factor. Our work demonstrates that triglycerides promote homeostasis by "buffering" specific fatty acids.
MeSH term(s)	Animals ; Carcinoma, Renal Cell/metabolism ; Cell Line ; Cell Survival/physiology ; Ceramides/metabolism ; Chromatography, Liquid ; Fatty Acids/blood ; Fatty Acids/metabolism ; Female ; Flow Cytometry ; Humans ; Hypoxia/blood ; Hypoxia/metabolism ; Kidney Neoplasms/metabolism ; Lipid Metabolism/physiology ; Mass Spectrometry ; Reverse Transcriptase Polymerase Chain Reaction ; Stearoyl-CoA Desaturase/metabolism ; Triglycerides/blood ; Triglycerides/metabolism
Chemical Substances	Ceramides ; Fatty Acids ; Triglycerides ; Stearoyl-CoA Desaturase (EC 1.14.19.1)
Language	English
Publishing date	2018-09-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2018.08.015
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Article ; Online: Macropinocytosis Renders a Subset of Pancreatic Tumor Cells Resistant to mTOR Inhibition.

Michalopoulou, Evdokia / Auciello, Francesca R / Bulusu, Vinay / Strachan, David / Campbell, Andrew D / Tait-Mulder, Jacqueline / Karim, Saadia A / Morton, Jennifer P / Sansom, Owen J / Kamphorst, Jurre J

Cell reports

2020 Volume 30, Issue 8, Page(s) 2729–2742.e4

Abstract: Pancreatic ductal adenocarcinoma (PDAC) features a near-universal mutation in KRAS. Additionally, the tumor suppressor PTEN is lost in ∼10% of patients, and in mouse models, this dramatically accelerates tumor progression. While oncogenic KRAS and ... ...

Abstract	Pancreatic ductal adenocarcinoma (PDAC) features a near-universal mutation in KRAS. Additionally, the tumor suppressor PTEN is lost in ∼10% of patients, and in mouse models, this dramatically accelerates tumor progression. While oncogenic KRAS and phosphatidylinositol 3-kinase (PI3K) cause divergent metabolic phenotypes individually, how they synergize to promote tumor metabolic alterations and dependencies remains unknown. We show that in KRAS-driven murine PDAC cells, loss of Pten strongly enhances both mTOR signaling and macropinocytosis. Protein scavenging alleviates sensitivity to mTOR inhibition by rescuing AKT phosphorylation at serine 473 and consequently cell proliferation. Combined inhibition of mTOR and lysosomal processing of internalized protein eliminates the macropinocytosis-mediated resistance. Our results indicate that mTORC2, rather than mTORC1, is an important regulator of protein scavenging and that protein-mediated resistance could explain the lack of effectiveness of mTOR inhibitors in certain genetic backgrounds. Concurrent inhibition of mTOR and protein scavenging might be a valuable therapeutic approach.
MeSH term(s)	Adenocarcinoma/pathology ; Animals ; Carcinoma, Pancreatic Ductal/pathology ; Cell Death ; Cell Line, Tumor ; Cell Proliferation ; Drug Resistance, Neoplasm ; Lysosomes/metabolism ; Mechanistic Target of Rapamycin Complex 2/metabolism ; Mice, Inbred C57BL ; Models, Biological ; PTEN Phosphohydrolase/metabolism ; Pancreatic Neoplasms/metabolism ; Pancreatic Neoplasms/pathology ; Phosphorylation ; Phosphoserine/metabolism ; Pinocytosis ; Proto-Oncogene Proteins c-akt/metabolism ; Proto-Oncogene Proteins p21(ras)/metabolism ; Signal Transduction ; TOR Serine-Threonine Kinases/antagonists & inhibitors ; TOR Serine-Threonine Kinases/metabolism ; Up-Regulation
Chemical Substances	KRAS protein, human ; Phosphoserine (17885-08-4) ; Mechanistic Target of Rapamycin Complex 2 (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; PTEN Phosphohydrolase (EC 3.1.3.67) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
Language	English
Publishing date	2020-02-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2020.01.080
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Article ; Online: Macropinocytosis Renders a Subset of Pancreatic Tumor Cells Resistant to mTOR Inhibition

Evdokia Michalopoulou / Francesca R. Auciello / Vinay Bulusu / David Strachan / Andrew D. Campbell / Jacqueline Tait-Mulder / Saadia A. Karim / Jennifer P. Morton / Owen J. Sansom / Jurre J. Kamphorst

Cell Reports, Vol 30, Iss 8, Pp 2729-2742.e

2020 Volume 4

Abstract: ... Michalopoulou et al. show that in pancreatic cancer cells with oncogenic KRAS and PTEN loss, scavenging ...

Abstract	Summary: Pancreatic ductal adenocarcinoma (PDAC) features a near-universal mutation in KRAS. Additionally, the tumor suppressor PTEN is lost in ∼10% of patients, and in mouse models, this dramatically accelerates tumor progression. While oncogenic KRAS and phosphatidylinositol 3-kinase (PI3K) cause divergent metabolic phenotypes individually, how they synergize to promote tumor metabolic alterations and dependencies remains unknown. We show that in KRAS-driven murine PDAC cells, loss of Pten strongly enhances both mTOR signaling and macropinocytosis. Protein scavenging alleviates sensitivity to mTOR inhibition by rescuing AKT phosphorylation at serine 473 and consequently cell proliferation. Combined inhibition of mTOR and lysosomal processing of internalized protein eliminates the macropinocytosis-mediated resistance. Our results indicate that mTORC2, rather than mTORC1, is an important regulator of protein scavenging and that protein-mediated resistance could explain the lack of effectiveness of mTOR inhibitors in certain genetic backgrounds. Concurrent inhibition of mTOR and protein scavenging might be a valuable therapeutic approach. : Michalopoulou et al. show that in pancreatic cancer cells with oncogenic KRAS and PTEN loss, scavenging of extracellular protein provides resistance against mTOR inhibition. Protein scavenging circumvents mTORC2 signaling by rescuing AKT phosphorylation. Additional treatment with AKT or lysosomal inhibitors strongly potentiates the effect of mTOR inhibitors. Keywords: AKT, cancer metabolism, macropinocytosis, metabolic scavenging, mTORC2, pancreatic ductal adenocarcinoma
Keywords	Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2020-02-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Triglycerides Promote Lipid Homeostasis during Hypoxic Stress by Balancing Fatty Acid Saturation

Daniel Ackerman / Sergey Tumanov / Bo Qiu / Evdokia Michalopoulou / Michelle Spata / Andrew Azzam / Hong Xie / M. Celeste Simon / Jurre J. Kamphorst

Cell Reports, Vol 24, Iss 10, Pp 2596-2605.e

2018 Volume 5

Abstract: Summary: Lipid droplets, which store triglycerides and cholesterol esters, are a prominent feature of clear cell renal cell carcinoma (ccRCC). Although their presence in ccRCC is critical for sustained tumorigenesis, their contribution to lipid ... ...

Abstract	Summary: Lipid droplets, which store triglycerides and cholesterol esters, are a prominent feature of clear cell renal cell carcinoma (ccRCC). Although their presence in ccRCC is critical for sustained tumorigenesis, their contribution to lipid homeostasis and tumor cell viability is incompletely understood. Here we show that disrupting triglyceride synthesis compromises the growth of both ccRCC tumors and ccRCC cells exposed to tumor-like conditions. Functionally, hypoxia leads to increased fatty acid saturation through inhibition of the oxygen-dependent stearoyl-CoA desaturase (SCD) enzyme. Triglycerides counter a toxic buildup of saturated lipids, primarily by releasing the unsaturated fatty acid oleate (the principal product of SCD activity) from lipid droplets into phospholipid pools. Disrupting this process derails lipid homeostasis, causing overproduction of toxic saturated ceramides and acyl-carnitines as well as activation of the NF-κB transcription factor. Our work demonstrates that triglycerides promote homeostasis by “buffering” specific fatty acids. : Tumors frequently experience hypoxia and serum limitation, which cause a harmful increase in fatty acid saturation. Studying kidney cancer, Ackerman et al. describe a protective role of lipid droplet-resident triglycerides: buffering of the cellular lipid saturation through exchange of mono-unsaturated fatty acids. Inhibiting triglyceride synthesis compromises solid tumor growth. Keywords: cancer metabolism, clear cell renal cell carcinoma, diglyceride acyltransferase, fatty acid saturation, hypoxia, lipid droplets, lipid homeostasis, lipidomics, stable isotope tracing, triglycerides
Keywords	Biology (General) ; QH301-705.5
Subject code	571 ; 572
Language	English
Publishing date	2018-09-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Acetate Recapturing by Nuclear Acetyl-CoA Synthetase 2 Prevents Loss of Histone Acetylation during Oxygen and Serum Limitation.

Bulusu, Vinay / Tumanov, Sergey / Michalopoulou, Evdokia / van den Broek, Niels J / MacKay, Gillian / Nixon, Colin / Dhayade, Sandeep / Schug, Zachary T / Vande Voorde, Johan / Blyth, Karen / Gottlieb, Eyal / Vazquez, Alexei / Kamphorst, Jurre J

Cell reports

2017 Volume 18, Issue 3, Page(s) 647–658

Abstract: Acetyl-CoA is a key metabolic intermediate with an important role in transcriptional regulation. The nuclear-cytosolic acetyl-CoA synthetase 2 (ACSS2) was found to sustain the growth of hypoxic tumor cells. It generates acetyl-CoA from acetate, but ... ...

Abstract	Acetyl-CoA is a key metabolic intermediate with an important role in transcriptional regulation. The nuclear-cytosolic acetyl-CoA synthetase 2 (ACSS2) was found to sustain the growth of hypoxic tumor cells. It generates acetyl-CoA from acetate, but exactly which pathways it supports is not fully understood. Here, quantitative analysis of acetate metabolism reveals that ACSS2 fulfills distinct functions depending on its cellular location. Exogenous acetate uptake is controlled by expression of both ACSS2 and the mitochondrial ACSS1, and ACSS2 supports lipogenesis. The mitochondrial and lipogenic demand for two-carbon acetyl units considerably exceeds the uptake of exogenous acetate, leaving it to only sparingly contribute to histone acetylation. Surprisingly, oxygen and serum limitation increase nuclear localization of ACSS2. We find that nuclear ACSS2 recaptures acetate released from histone deacetylation for recycling by histone acetyltransferases. Our work provides evidence for limited equilibration between nuclear and cytosolic acetyl-CoA and demonstrates that ACSS2 retains acetate to maintain histone acetylation.
MeSH term(s)	Acetate-CoA Ligase/antagonists & inhibitors ; Acetate-CoA Ligase/genetics ; Acetate-CoA Ligase/metabolism ; Acetates/chemistry ; Acetates/metabolism ; Acetyl Coenzyme A/metabolism ; Acetylation ; Carbon Isotopes/chemistry ; Cell Hypoxia ; Cell Line, Tumor ; Cell Nucleus/enzymology ; Chromatography, High Pressure Liquid ; Culture Media/chemistry ; Histones/metabolism ; Humans ; Mass Spectrometry ; Metabolome ; Microscopy, Fluorescence ; Mitochondria/metabolism ; RNA Interference ; RNA, Small Interfering/metabolism ; Serum/chemistry
Chemical Substances	Acetates ; Carbon Isotopes ; Culture Media ; Histones ; RNA, Small Interfering ; Acetyl Coenzyme A (72-89-9) ; Acetate-CoA Ligase (EC 6.2.1.1)
Language	English
Publishing date	2017-01-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2016.12.055
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Article ; Online: Rho Kinase Inhibition by AT13148 Blocks Pancreatic Ductal Adenocarcinoma Invasion and Tumor Growth.

Rath, Nicola / Munro, June / Cutiongco, Marie Francene / Jagiełło, Alicja / Gadegaard, Nikolaj / McGarry, Lynn / Unbekandt, Mathieu / Michalopoulou, Evdokia / Kamphorst, Jurre J / Sumpton, David / Mackay, Gillian / Vennin, Claire / Pajic, Marina / Timpson, Paul / Olson, Michael F

Cancer research

2018 Volume 78, Issue 12, Page(s) 3321–3336

Abstract: The high mortality of pancreatic cancer demands that new therapeutic avenues be developed. The orally available small-molecule inhibitor AT13148 potently inhibits ROCK1 and ROCK2 kinases that regulate the actomyosin cytoskeleton. We previously reported ... ...

Abstract	The high mortality of pancreatic cancer demands that new therapeutic avenues be developed. The orally available small-molecule inhibitor AT13148 potently inhibits ROCK1 and ROCK2 kinases that regulate the actomyosin cytoskeleton. We previously reported that ROCK kinase expression increases with human and mouse pancreatic cancer progression and that conditional ROCK activation accelerates mortality in a genetically modified
MeSH term(s)	1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives ; 2-Hydroxyphenethylamine/analogs & derivatives ; 2-Hydroxyphenethylamine/pharmacology ; 2-Hydroxyphenethylamine/therapeutic use ; Amides/pharmacology ; Amides/therapeutic use ; Animals ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Carcinoma, Pancreatic Ductal/drug therapy ; Carcinoma, Pancreatic Ductal/pathology ; Cell Line, Tumor/transplantation ; Cell Movement/drug effects ; Disease Models, Animal ; Female ; HEK293 Cells ; Humans ; Male ; Mice ; Neoplasm Invasiveness/pathology ; Neoplasm Invasiveness/prevention & control ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/pathology ; Phosphorylation/drug effects ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Pyrazoles/pharmacology ; Pyrazoles/therapeutic use ; Pyridines/pharmacology ; Pyridines/therapeutic use ; Signal Transduction/drug effects ; rho-Associated Kinases/antagonists & inhibitors ; rho-Associated Kinases/metabolism
Chemical Substances	2-methyl-1-((4-methyl-5-isoquinolinyl)sulfonyl)homopiperazine ; AT13148 ; Amides ; Protein Kinase Inhibitors ; Pyrazoles ; Pyridines ; Y 27632 (138381-45-0) ; 2-Hydroxyphenethylamine (7568-93-6) ; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine (84477-87-2) ; rho-Associated Kinases (EC 2.7.11.1)
Language	English
Publishing date	2018-04-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-17-1339
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Article ; Online: Acetate Recapturing by Nuclear Acetyl-CoA Synthetase 2 Prevents Loss of Histone Acetylation during Oxygen and Serum Limitation

Vinay Bulusu / Sergey Tumanov / Evdokia Michalopoulou / Niels J. van den Broek / Gillian MacKay / Colin Nixon / Sandeep Dhayade / Zachary T. Schug / Johan Vande Voorde / Karen Blyth / Eyal Gottlieb / Alexei Vazquez / Jurre J. Kamphorst

Cell Reports, Vol 18, Iss 3, Pp 647-

2017 Volume 658

Abstract	Acetyl-CoA is a key metabolic intermediate with an important role in transcriptional regulation. The nuclear-cytosolic acetyl-CoA synthetase 2 (ACSS2) was found to sustain the growth of hypoxic tumor cells. It generates acetyl-CoA from acetate, but exactly which pathways it supports is not fully understood. Here, quantitative analysis of acetate metabolism reveals that ACSS2 fulfills distinct functions depending on its cellular location. Exogenous acetate uptake is controlled by expression of both ACSS2 and the mitochondrial ACSS1, and ACSS2 supports lipogenesis. The mitochondrial and lipogenic demand for two-carbon acetyl units considerably exceeds the uptake of exogenous acetate, leaving it to only sparingly contribute to histone acetylation. Surprisingly, oxygen and serum limitation increase nuclear localization of ACSS2. We find that nuclear ACSS2 recaptures acetate released from histone deacetylation for recycling by histone acetyltransferases. Our work provides evidence for limited equilibration between nuclear and cytosolic acetyl-CoA and demonstrates that ACSS2 retains acetate to maintain histone acetylation.
Keywords	acetate ; acetyl-CoA synthetase 2 ; cancer metabolism ; enzyme localization ; histone acetylation ; histone deacetylation ; hypoxia ; lipogenesis ; metabolite compartmentalization ; stable isotope tracing ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2017-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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