An integrated functional genomics and metabolomics approach for defining poor prognosis in human neuroendocrine cancers

作者：Ippolito JE; Xu J; Jain SJ; Moulder K; Mennerick S; Crowley JR; Townsend RR; Gordon JI^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2005, 102(28): 9901-9906.

DOI：10.1073/pnas.0500756102

• GABA signaling
• MS
• metastatic neuroendocrine cancers
• polyamine metabolism
• transcriptome-directed metabolomics

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.

• 出版日期2005-7-12