Linkage between cellular communications, energy utilization, and proliferation in metastatic neuroendocrine cancers.
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.
Ippolito
Joseph E
JE
Center for Genome Sciences, Washington University, St. Louis, MO 63108, USA.
Merritt
Matthew E
ME
Bäckhed
Fredrik
F
Moulder
Krista L
KL
Mennerick
Steven
S
Manchester
Jill K
JK
Gammon
Seth T
ST
Piwnica-Worms
David
D
Gordon
Jeffrey I
JI
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
D011956:Receptors, Cell Surface; D005680:gamma-Aminobutyric Acid; D002118:Calcium