title: Linkage between cellular communications, energy utilization, and proliferation in metastatic neuroendocrine cancers.
abstract: To identify metabolic features that support the aggressive behavior of human neuroendocrine (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 Abp1, an enzyme involved in NE cell GABA metabolism, (ii) carbidopa, an inhibitor of dopa decarboxylase which functions upstream of Abp1, plus (iii) flumazenil, a benzodiazepine antagonist that binds to GABA(A) 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.
authors.affiliation: Center for Genome Sciences, Washington University, St. Louis, MO 63108, USA.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Ippolito
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Merritt
authors.forename: Fredrik
authors.initials: F
authors.lastname: Bäckhed
authors.forename: Krista L
authors.initials: KL
authors.lastname: Moulder
authors.forename: Steven
authors.initials: S
authors.lastname: Mennerick
authors.forename: Jill K
authors.initials: JK
authors.lastname: Manchester
authors.forename: Seth T
authors.initials: ST
authors.lastname: Gammon
authors.forename: David
authors.initials: D
authors.lastname: Piwnica-Worms
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Gordon
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology*; D049109:Cell Proliferation; D002952:Citric Acid Cycle / Q000502:physiology; D004734:Energy Metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D018358:Neuroendocrine Tumors / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D019906:Nuclear Magnetic Resonance, Biomolecular; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011956:Receptors, Cell Surface / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D011956:Receptors, Cell Surface; D005680:gamma-Aminobutyric Acid; D002118:Calcium