Contextual inhibition of fatty acid synthesis by metformin involves glucose-derived acetyl-CoA and cholesterol in pancreatic tumor cells

Mary Jo Cantoria, László G. Boros, Emmanuelle J. Meuillet

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Metformin, a generic glucose lowering drug, inhibits cancer growth expressly in models that employ high fat/cholesterol intake and/or low glucose availability. Here we use a targeted tracer fate association study (TTFAS) to investigate how cholesterol and metformin administration regulates glucose-derived intermediary metabolism and macromolecule synthesis in pancreatic cancer cells. Wild type K-ras BxPC-3 and HOM: GGT(Gly) → TGT(Cys) K12 transformed MIA PaCa-2 adenocarcinoma cells were cultured in the presence of [1,2-13C2]-d-glucose as the single tracer for 24 h and treated with either 100 μM metformin (MET), 1 mM cholesteryl hemisuccinate (CHS), or the dose matching combination of MET and CHS (CHS-MET). Wild type K-ras cells used 11.43 % (SD = ±0.32) of new acetyl-CoA for palmitate synthesis that was derived from glucose, while K-ras mutated MIA PaCa-2 cells shuttled less than half as much, 5.47 % [SD = ±0.28 (P < 0.01)] of this precursor towards FAS. Cholesterol treatment almost doubled glucose-derived acetyl-CoA enrichment to 9.54 % (SD = ±0.24) and elevated the fraction of new palmitate synthesis by over 2.5-fold in MIA PaCa-2 cells; whereby 100 μM MET treatment resulted in a 28 % inhibitory effect on FAS. Therefore, acetyl-CoA shuttling towards its carboxylase, from thiolase, produces contextual synthetic inhibition by metformin of new palmitate production. Thereby, metformin, mutated K-ras and high cholesterol each contributes to limit new fatty acid and potentially cell membrane synthesis, demonstrating a previously unknown mechanism for inhibiting cancer growth during the metabolic syndrome.

Original languageEnglish (US)
Pages (from-to)91-104
Number of pages14
JournalMetabolomics
Volume10
Issue number1
DOIs
StatePublished - Feb 1 2014

Keywords

  • C glucose-derived acetyl-CoA
  • Cholesterol
  • Contextual drug effect
  • System-wide association study
  • TTFAS
  • Targeted tracer fate association study

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Clinical Biochemistry

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