An integrated functional genomics and metabolomics approach for defining poor prognosis in human neuroendocrine cancers.
Human neuroendocrine (NE) cancers range from relatively indolent to highly aggressive. In this study, we combine functional genomics with metabolomics to identify features of NE cancers associated with a poor outcome. Analysis of GeneChip datasets of primary prostate tumors, as well as lymph node and liver metastases from transgenic mice with a NE cell cancer, plus derived NE cell lines yielded a signature of 446 genes whose expression is enriched in neoplastic mouse prostatic NE cells. This signature was used for in silico metabolic reconstructions of NE cell metabolism, directed liquid chromatography/tandem MS analysis of metabolites in prostatic NE tumors and cell lines, and analysis of GeneChip datasets of human NE tumors with good or poor prognoses. The results indicate that a distinguishing feature of poor-prognosis NE tumors is a glutamic acid decarboxylase-independent pathway for production of GABA and a pathway for production of imidazole-4-acetate that involves dopa decarboxylase and a membrane-associated amine oxidase, amiloride-binding protein 1. Electrophysiological studies disclosed that imidazole-4-acetate can bind and activate GABA(A) receptors expressed by transformed NE cells, thus providing a previously uncharacterized paradigm for NE tumor cell signaling. Transcriptional, metabolic, and electrophysiologic features of transformed mouse NE cells are also evident in neural progenitor cells.
Center for Genome Sciences and Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Joseph E
JE
Ippolito
Jian
J
Xu
Sanjay
S
Jain
Krista
K
Moulder
Steven
S
Mennerick
Jan R
JR
Crowley
R Reid
RR
Townsend
Jeffrey I
JI
Gordon
D000818:Animals; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D004594:Electrophysiology; D015870:Gene Expression; D023281:Genomics / Q000379:methods*; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D008822:Mice, Transgenic; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D018079:Receptors, GABA / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D005680:gamma-Aminobutyric Acid / Q000096:biosynthesis
D007093:Imidazoles; D018079:Receptors, GABA; D005680:gamma-Aminobutyric Acid; C005954:imidazoleacetic acid