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Journal of Lipid Research, Vol. 45, 308-316, February 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Dietary -linolenic acid reduces COX-2 expression and induces apoptosis of hepatoma cells

A. Vecchini^*, V. Ceccarelli^*, F. Susta^*, P. Caligiana^*, P. Orvietani^*, L. Binaglia^1,*, G. Nocentini, C. Riccardi, G. Calviello, P. Palozza, N. Maggiano and P. Di Nardo^**

^* Department of Internal Medicine, Section of Biochemistry, University of Perugia, Perugia, Italy
Department of Clinical and Experimental Medicine, Section of Pharmacology, University of Perugia, Perugia, Italy
Institute of General Pathology, Catholic University, Rome, Italy
^** Department of Internal Medicine, Laboratory of Cellular and Molecular Cardiology, University of Roma "Tor Vergata," Rome, Italy

¹ To whom correspondence should be addressed. e-mail: binaglia{at}unipg.it

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 -3 and -6 polyunsaturated fatty acids (PUFAs) depress FAS expression in liver, although epidemiological and experimental reports attribute antitumor properties only to -3 PUFA. Therefore, we investigated whether lipogenic gene expression in tumor cells is differently regulated by -6 and -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 -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 -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 -linolenic acid-enriched diet correlated with a decrease in arachidonate content in hepatoma cells and decreased cyclooxygenase-2 expression.

Abbreviations: ACC, acetyl-CoA carboxylase; C/EBP, CCAAT enhancer binding protein; COX-2, cyclooxygenase-2; CPT-1, carnitine palmitoyltransferase-1; FAS, fatty acid synthetase; PPAR, peroxisome proliferator-activated receptor-; SCAP, sterol regulatory element binding protein-1 cleavage activating protein; S1P, site-1 protease; S2P, site-2 protease; SREBP-1, sterol regulatory element binding protein-1

Supplementary key words cyclooxygenase-2 • polyunsaturated fatty acids • sterol regulatory element binding protein 1

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