Impact of mitochondrial beta-oxidation in fatty acid-mediated inhibition of glioma cell proliferation.
Tetradecylthioacetic acid (TTA), which cannot be beta-oxidized, exerts growth-limiting properties in glioma cells. In order to investigate the importance of modulated lipid metabolism and alterations in mitochondrial properties in this cell death process, we incubated glioma cells both with TTA and the oxidizable fatty acid palmitic acid (PA), in the presence of L-carnitine and the carnitine palmitoyltransferase inhibitors etomoxir and aminocarnitine. L-carnitine partly abolished the PA-mediated growth reduction of glioma cells, whereas etomoxir and aminocarnitine enhanced the antiproliferative effect of PA. The production of acid-soluble products increased and the incorporation of PA into glycerolipids decreased after L-carnitine supplementation. L-carnitine was found to enhance the antiproliferative effect of TTA, but did not affect the incorporation of TTA into glycerolipids, or ceramide. PDMP, sphingosine 1-phosphate, desipramine, fumonisin B(1), and L-cycloserine were able not to rescue the glioma cells from PA and TTA-induced growth inhibition, suggesting that increased ceramide production is not important in the growth reduction. TTA-mediated growth inhibition was accompanied with an increased uptake of PA and increased incorporation of PA into triacylglycerol (TG). Our data suggest that mitochondrial functions are involved in fatty acid-mediated growth inhibition. Whether there is a causal relationship between TG accumulation and the apoptotic process remains to be determined.
Berge
Kjetil
K
Department of Clinical Biochemistry, Haukeland Hospital, University of Bergen, N-5021 Bergen, Norway. kjetil.berge@ikb.uib.no
Tronstad
Karl Johan
KJ
Bohov
Pavol
P
Madsen
Lise
L
Berge
Rolf K
RK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002331:Carnitine / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004852:Epoxy Compounds / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism* / Q000494:pharmacology*; D008401:Gas Chromatography-Mass Spectrometry; D005910:Glioma / Q000378:metabolism* / Q000473:pathology*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D010084:Oxidation-Reduction; D019308:Palmitic Acid / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D013107:Sphingolipids / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D013440:Sulfides / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D004852:Epoxy Compounds; D005227:Fatty Acids; D013107:Sphingolipids; D013440:Sulfides; D019308:Palmitic Acid; C062078:1-(carboxymethylthio)tetradecane; D005978:Glutathione; C054207:etomoxir; D002331:Carnitine