Dietary alpha-linolenic acid reduces COX-2 expression and induces apoptosis of hepatoma cells.
Fatty acid synthetase (FAS) is overexpressed in various tumor tissues, and its inhibition and/or malonyl-CoA accumulation have been correlated to apoptosis of tumor cells. It is widely recognized that both omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) depress FAS expression in liver, although epidemiological and experimental reports attribute antitumor properties only to omega-3 PUFA. Therefore, we investigated whether lipogenic gene expression in tumor cells is differently regulated by omega-6 and omega-3 PUFAs. Morris hepatoma 3924A cells were implanted subcutaneously in the hind legs of ACI/T rats preconditioned with high-lipid diets enriched with linoleic acid or alpha-linolenic acid. Both-high lipid diets depressed the expression of FAS and acetyl-CoA carboxylase in tumor tissue, this effect correlating with a decrease in the mRNA level of their common sterol regulatory element binding protein-1 transcription factor. Hepatoma cells grown in rats on either diet did not accumulate malonyl-CoA. Apoptosis of hepatoma cells was induced by the alpha-linolenic acid-enriched diet but not by the linoleic acid-enriched diet. Therefore, in this experimental model, apoptosis is apparently independent of the inhibition of fatty acid synthesis and of malonyl-CoA cytotoxicity. Conversely, it was observed that apoptosis induced by the alpha-linolenic acid-enriched diet correlated with a decrease in arachidonate content in hepatoma cells and decreased cyclooxygenase-2 expression.
Vecchini
A
A
Department of Internal Medicine, Section of Biochemistry, University of Perugia, Perugia, Italy.
Ceccarelli
V
V
Susta
F
F
Caligiana
P
P
Orvietani
P
P
Binaglia
L
L
Nocentini
G
G
Riccardi
C
C
Calviello
G
G
Palozza
P
P
Maggiano
N
N
Di Nardo
P
P
D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D051546:Cyclooxygenase 2; D004032:Diet; D004042:Dietary Fats, Unsaturated; D015536:Down-Regulation / Q000235:genetics; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism; D043371:Fatty Acids, Omega-6 / Q000235:genetics / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics*; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics*; D051381:Rats; D017962:alpha-Linolenic Acid / Q000008:administration & dosage* / Q000378:metabolism
D022762:CCAAT-Enhancer-Binding Proteins; D004042:Dietary Fats, Unsaturated; D043371:Fatty Acids, Omega-6; D005231:Fatty Acids, Unsaturated; D007527:Isoenzymes; D017962:alpha-Linolenic Acid; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D064429:Fatty Acid Synthases; D000103:Acetyl-CoA Carboxylase