Contextual inhibition of fatty acid synthesis by metformin involves glucose-derived acetyl-CoA and cholesterol in pancreatic tumor cells.
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-rasBxPC-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-rascells used 11.43 % (SD = ±0.32) of new acetyl-CoA for palmitate synthesis that was derived from glucose, while K-rasmutated 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-rasand 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.
Department of Nutritional Sciences, The University of Arizona, 1177 East 4th Street, Shantz Building #309, P.O. Box 210038, Tucson, AZ 85721-0038 USA.
Mary Jo
MJ
Cantoria
SiDMAP, LLC, 2990 South Sepulveda Blvd. #300B, Los Angeles, CA 90064 USA.|Department of Pediatrics, Los Angeles Biomedical Research Institute at the Harbor-UCLA Medical Center, 1124 West Carson Street, Torrance, CA 90502 USA.
László G
LG
Boros
The University of Arizona Cancer Center, 1515 N. Campbell Ave Levy Building, Tucson, AZ 85724 USA.
Emmanuelle J
EJ
Meuillet
13C glucose-derived acetyl-CoA; Cholesterol; Contextual drug effect; System-wide association study; TTFAS; Targeted tracer fate association study