Linkage between cellular communications, energy utilization, and proliferation in metastatic neuroendocrine cancers
Linkage between cellular communications, energy utilization, and proliferation in metastatic neuroendocrine cancers
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DOI：
10.1073/pnas.0605207103
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发表时间：
2006-08-15
影响因子：
11.1
通讯作者：
Gordon, Jeffrey I.
中科院分区：
文献类型：
--
作者：
Ippolito, Joseph E.;Merritt, Matthew E.;Gordon, Jeffrey I.
To identify metabolic features that support the aggressive behavior of human neuroenclocrine (NE) cancers, we examined metastatic prostate NE tumors and derived prostate NE cancer (PNEC) cell lines from a transgenic mouse model using a combination of magic angle spinning NMR spectroscopy, in silico predictions of biotransformations that observed metabolites may undergo, biochemical tests of these predictions, and electrophysiological/calcium imaging studies. Malignant NE cells undergo excitation and increased proliferation when their GABA(A), glutamate, and/or glycine receptors are stimulated, use glutamate and GABA as substrates for NADH biosynthesis, and produce propylene glycol, a precursor of pyruvate derived from glycine that increases levels of circulating free fatty acids through extra-NE cell effects. Treatment of nude mice containing PNEC tumor xenografts with (i) amiloride, a diuretic that inhibits Abpl, an enzyme involved in NE cell GABA metabolism, (ii) carbiclopa, an inhibitor of dopa decarboxylasewhich functions upstream of Abpl, plus (iii) flumazenil, a benzodiazepine antagonist that binds to GABAA receptors, leads to significant reductions in tumor growth. These findings may be generally applicable: GeneChip data sets from 471 human neoplasms revealed that components of GABA metabolic pathways, including ABP1, exhibit statistically significant increases in their expression in NE and non-NE cancers.
