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A functional metabolomics approach t...

Ippolito, Joseph Edward.

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A functional metabolomics approach to prostate and neuroendocrine carcinogenesis.

Record Type:	Electronic resources : Monograph/item
Title/Author:	A functional metabolomics approach to prostate and neuroendocrine carcinogenesis./
Author:	Ippolito, Joseph Edward.
Description:	350 p.
Notes:	Source: Dissertation Abstracts International, Volume: 68-06, Section: B, page: .
Contained By:	Dissertation Abstracts International68-06B.
Subject:	Chemistry, Biochemistry. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3268042
ISBN:	9780549070160

A functional metabolomics approach to prostate and neuroendocrine carcinogenesis.
Ippolito, Joseph Edward.

A functional metabolomics approach to prostate and neuroendocrine carcinogenesis. - 350 p.

Source: Dissertation Abstracts International, Volume: 68-06, Section: B, page: .

Thesis (Ph.D.)--Washington University in St. Louis, 2007.

Human neuroendocrine (NE) cancers range from relatively indolent to highly aggressive. This thesis introduces novel methods to identify metabolomic features of NE cancers associated with a poor outcome. One method represents a "forward metabolomics approach": it consists of transcriptome-directed metabolomics and uses the high throughput of DNA microarrays to acquire a profile of transcripts whose levels are enriched in metastatic prostate NE tumors in transgenic mice plus derived prostate NE cancer (PNEC) cell lines compared to normal prostate. This transcript 'signature' was then used for (i) in silico metabolic reconstructions of NE cell metabolism, (ii) directed liquid chromatography-tandem MS analysis of metabolites in mouse prostatic NE tumors and PNEC cells, and (iii) analysis of microarray datasets obtained from human NE tumors with good or poor prognoses. The results indicated that a distinguishing feature of poor-prognosis NE tumors is a glutamic acid decarboxylase-independent pathway for production of gamma-aminobutyric acid (GABA), and a pathway for production of imidazole-4-acetate involving dopa decarboxylase and a membrane-associated amine oxidase, amiloride-binding protein 1 (ABP1). Electrophysiological studies disclosed that PNEC cells express functional glutamate, glycine and GABA A receptors, and that GABA and imidazole-4-acetate can bind and activate GABAA receptors, thus providing a previously uncharacterized paradigm for NE tumor cell signaling. I demonstrated that GABA also plays a role in intracellular energy production, as PNEC cells have the ability to convert GABA to succinate through a pathway known as the GABA shunt of the TCA cycle. A parallel "reverse metabolomics approach" was also taken using magic angle spinning (MAS) NMR to profile metabolites in prostate NE tumors and correlate the results with in silico metabolic reconstructions from microarray studies. MAS-NMR disclosed that prostate NE cancer cells accumulate large amounts of propylene glycol, a precursor to pyruvate. In silico metabolic reconstructions indicated that ABP1 was part of a propylene glycol biosynthetic pathway from glycine. Together, these findings disclose a potential link between cellular signaling and energy utilization in poor prognosis cancers. Furthermore, I have discovered that transcriptional and metabolic features of transformed mouse NE cells are evident in hematopoietic and neural stem cell populations, as well as in cancers with a non-NE origin.

ISBN: 9780549070160Subjects--Topical Terms:

1017722
Chemistry, Biochemistry.

A functional metabolomics approach to prostate and neuroendocrine carcinogenesis.
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245 1 2 $a A functional metabolomics approach to prostate and neuroendocrine carcinogenesis.
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500 $a Source: Dissertation Abstracts International, Volume: 68-06, Section: B, page: .
500 $a Adviser: Jeffrey I. Gordon.
502 $a Thesis (Ph.D.)--Washington University in St. Louis, 2007.
520 $a Human neuroendocrine (NE) cancers range from relatively indolent to highly aggressive. This thesis introduces novel methods to identify metabolomic features of NE cancers associated with a poor outcome. One method represents a "forward metabolomics approach": it consists of transcriptome-directed metabolomics and uses the high throughput of DNA microarrays to acquire a profile of transcripts whose levels are enriched in metastatic prostate NE tumors in transgenic mice plus derived prostate NE cancer (PNEC) cell lines compared to normal prostate. This transcript 'signature' was then used for (i) in silico metabolic reconstructions of NE cell metabolism, (ii) directed liquid chromatography-tandem MS analysis of metabolites in mouse prostatic NE tumors and PNEC cells, and (iii) analysis of microarray datasets obtained from human NE tumors with good or poor prognoses. The results indicated that a distinguishing feature of poor-prognosis NE tumors is a glutamic acid decarboxylase-independent pathway for production of gamma-aminobutyric acid (GABA), and a pathway for production of imidazole-4-acetate involving dopa decarboxylase and a membrane-associated amine oxidase, amiloride-binding protein 1 (ABP1). Electrophysiological studies disclosed that PNEC cells express functional glutamate, glycine and GABA A receptors, and that GABA and imidazole-4-acetate can bind and activate GABAA receptors, thus providing a previously uncharacterized paradigm for NE tumor cell signaling. I demonstrated that GABA also plays a role in intracellular energy production, as PNEC cells have the ability to convert GABA to succinate through a pathway known as the GABA shunt of the TCA cycle. A parallel "reverse metabolomics approach" was also taken using magic angle spinning (MAS) NMR to profile metabolites in prostate NE tumors and correlate the results with in silico metabolic reconstructions from microarray studies. MAS-NMR disclosed that prostate NE cancer cells accumulate large amounts of propylene glycol, a precursor to pyruvate. In silico metabolic reconstructions indicated that ABP1 was part of a propylene glycol biosynthetic pathway from glycine. Together, these findings disclose a potential link between cellular signaling and energy utilization in poor prognosis cancers. Furthermore, I have discovered that transcriptional and metabolic features of transformed mouse NE cells are evident in hematopoietic and neural stem cell populations, as well as in cancers with a non-NE origin.
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