Linkage between cellular communications, energy utilization, and proliferation in metastatic neuroendocrine cancers

Joseph E. Ippolito, Matthew E. Merrit, Fredrik Bäckhed, Krista L. Moulder, Steven Mennerick, Jill K. Manchester, Seth T. Gammon, David Piwnica-Worms, Jeffrey I. Gordon

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

To identify metabolic features that support the aggressive behavior of human neuroendocrine (HE) 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 GABAA, 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 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.

Original languageEnglish (US)
Pages (from-to)12505-12510
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number33
DOIs
StatePublished - Aug 15 2006

Keywords

  • Electrophysiology
  • GABA signaling and shunt
  • Magic angle spinning-NMR
  • Metabolome-directed cancer therapy
  • Metabolomics

ASJC Scopus subject areas

  • General

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    Ippolito, J. E., Merrit, M. E., Bäckhed, F., Moulder, K. L., Mennerick, S., Manchester, J. K., Gammon, S. T., Piwnica-Worms, D., & Gordon, J. I. (2006). Linkage between cellular communications, energy utilization, and proliferation in metastatic neuroendocrine cancers. Proceedings of the National Academy of Sciences of the United States of America, 103(33), 12505-12510. https://doi.org/10.1073/pnas.0605207103