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Estradiol stimulates the biosynthetic pathways of breast cancer cells: Detection by metabolic flux analysis

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Title: Estradiol stimulates the biosynthetic pathways of breast cancer cells: Detection by metabolic flux analysis
Authors: Forbes, Neil S. forbes@ecs.umass.edu, Meadows, Adam L.1, Clark, Douglas S.1, Blanch, Harvey W.1
Source: Metabolic Engineering. Nov2006, Vol. 8 Issue 6, p639-652. 14p.
Subjects: Cancer treatment, Nuclear magnetic resonance, Estrogen, Magnetic resonance
Abstract: Abstract: Selective estrogen receptor (ER) modulators are highly successful breast cancer therapies, but they are not effective in patients with ER negative and selective estrogen receptor modulator (SERM)-resistant tumors. Understanding the mechanisms of estrogen-stimulated proliferation may provide a route to design estrogen-independent therapies that would be effective in these patients. In this study, metabolic flux analysis was used to determine the intracellular fluxes that are significantly affected by estradiol stimulation in MCF-7 breast cancer cells. Intracellular fluxes were calculated from nuclear magnetic resonance (NMR)-generated isotope enrichment data and extracellular metabolite fluxes, using a specific flux analysis algorithm. The metabolic pathway model used by the algorithm includes glycolysis, the tricarboxylic acid cycle (TCA cycle), the pentose phosphate pathway, glutamine catabolism, pyruvate carboxylase, and malic enzyme. The pathway model also incorporates mitochondrial compartmentalization and reversible trans-mitochondrial membrane reactions to more accurately describe the role of mitochondria in cancer cell proliferation. Flux results indicate that estradiol significantly increases carbon flow through the pentose phosphate pathway and increases glutamine consumption. In addition, intra-mitochondrial malic enzyme was found to be inactive and the malate-aspartate shuttle (MAS) was only minimally active. The inactivity of these enzymes indicates that glutamine is not oxidized within mitochondria, but is consumed primarily to provide biosynthetic precursors. The excretion of glutamine carbons from the mitochondria has the secondary effect of limiting nicotinamide adenine dinucleotide (NADH) recycle, resulting in NADH buildup in the cytosol and the excretion of lactate. The observed dependence of breast cancer cells on pentose phosphate pathway activity and glutamine consumption for estradiol-stimulated biosynthesis suggests that these pathways may be targets for estrogen-independent breast cancer therapies. [Copyright &y& Elsevier]
Copyright of Metabolic Engineering is the property of Academic Press Inc. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Estradiol stimulates the biosynthetic pathways of breast cancer cells: Detection by metabolic flux analysis
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  Data: <searchLink fieldCode="AR" term="%22Forbes%2C+Neil+S%2E%22">Forbes, Neil S.</searchLink><i> forbes@ecs.umass.edu</i><br /><searchLink fieldCode="AR" term="%22Meadows%2C+Adam+L%2E%22">Meadows, Adam L.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Clark%2C+Douglas+S%2E%22">Clark, Douglas S.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Blanch%2C+Harvey+W%2E%22">Blanch, Harvey W.</searchLink><relatesTo>1</relatesTo>
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  Data: <searchLink fieldCode="JN" term="%22Metabolic+Engineering%22">Metabolic Engineering</searchLink>. Nov2006, Vol. 8 Issue 6, p639-652. 14p.
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  Data: <searchLink fieldCode="DE" term="%22Cancer+treatment%22">Cancer treatment</searchLink><br /><searchLink fieldCode="DE" term="%22Nuclear+magnetic+resonance%22">Nuclear magnetic resonance</searchLink><br /><searchLink fieldCode="DE" term="%22Estrogen%22">Estrogen</searchLink><br /><searchLink fieldCode="DE" term="%22Magnetic+resonance%22">Magnetic resonance</searchLink>
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  Data: Abstract: Selective estrogen receptor (ER) modulators are highly successful breast cancer therapies, but they are not effective in patients with ER negative and selective estrogen receptor modulator (SERM)-resistant tumors. Understanding the mechanisms of estrogen-stimulated proliferation may provide a route to design estrogen-independent therapies that would be effective in these patients. In this study, metabolic flux analysis was used to determine the intracellular fluxes that are significantly affected by estradiol stimulation in MCF-7 breast cancer cells. Intracellular fluxes were calculated from nuclear magnetic resonance (NMR)-generated isotope enrichment data and extracellular metabolite fluxes, using a specific flux analysis algorithm. The metabolic pathway model used by the algorithm includes glycolysis, the tricarboxylic acid cycle (TCA cycle), the pentose phosphate pathway, glutamine catabolism, pyruvate carboxylase, and malic enzyme. The pathway model also incorporates mitochondrial compartmentalization and reversible trans-mitochondrial membrane reactions to more accurately describe the role of mitochondria in cancer cell proliferation. Flux results indicate that estradiol significantly increases carbon flow through the pentose phosphate pathway and increases glutamine consumption. In addition, intra-mitochondrial malic enzyme was found to be inactive and the malate-aspartate shuttle (MAS) was only minimally active. The inactivity of these enzymes indicates that glutamine is not oxidized within mitochondria, but is consumed primarily to provide biosynthetic precursors. The excretion of glutamine carbons from the mitochondria has the secondary effect of limiting nicotinamide adenine dinucleotide (NADH) recycle, resulting in NADH buildup in the cytosol and the excretion of lactate. The observed dependence of breast cancer cells on pentose phosphate pathway activity and glutamine consumption for estradiol-stimulated biosynthesis suggests that these pathways may be targets for estrogen-independent breast cancer therapies. [Copyright &y& Elsevier]
– Name: AbstractSuppliedCopyright
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  Data: <i>Copyright of Metabolic Engineering is the property of Academic Press Inc. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1016/j.ymben.2006.06.005
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      – SubjectFull: Estrogen
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              Text: Nov2006
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