Mechanism for the antitumor and anticachectic effects of n-3 fatty acids.
Dietary intake of the n-6 fatty acid (FA) linoleic acid (LA) has a strong growth-promoting effect on many rodent tumors and human tumor xenografts grown in immunodeficient rodents. n-3 FAs such as alpha-linolenic and eicosapentaenoic acids (EPAs), which differ from LA and arachidonic acid, respectively, by only a single double bond in the n-3 position, are recognized cancer chemopreventive and anticachectic agents. Understanding how this seemingly small structural difference leads to such remarkable functional differences has been a challenge. In a previous study, we showed that LA uptake, [3H]thymidine incorporation into DNA, and total DNA content were decreased in tissue-isolated hepatoma 7288CTC perfused in situ with arterial blood containing alpha-linolenic acid, EPA, or docosahexaenoic acids. The Ki for the inhibition of LA uptake and [3H]thymidine incorporation by alpha-linolenic acid was 0.18 and 0.25 mM, respectively. Here we show that the addition of alpha-linolenic acid or EPA to arterial blood inhibits tumor FA uptake, including LA, and the subsequent conversion of LA to the mitogen 13-hydroxyoctadecadienoic acid (13-HODE) in vivo and during perfusion in situ. [3H]Thymidine incorporation during perfusion in situ was also inhibited. Addition of 13-HODE to the arterial blood reversed the inhibition of [3H]thymidine incorporation but had no effect on FA uptake. These two n-3 FAs also inhibited FA transport in inguinal fat pads in vivo and during perfusion in situ in fed (FA uptake) and fasted (FA release) rats. The effects of EPA and talinolenic acid on transport of saturated, monounsaturated, and n-6 polyunsaturated FAs in hepatoma 7288CTC and inguinal fat pads during perfusion in situ were reversed by the addition of forskolin (1 microM), pertussis toxin (0.5 microg/ml), or 8-bromo-cyclic AMP (10 microM) to the arterial blood. We conclude that the antitumor and anticachectic effects of n-3 FAs on hepatoma 7288CTC and inguinal fat pads in vivo result from an inhibition of FA transport. These inhibitions are mediated by a putative n-3 FA receptor via a Gi protein-coupled signal transduction pathway that decreases intracellular cyclic AMP. A specific decrease in LA uptake and its conversion to the mitogen 13-HODE causes the tumor growth inhibition.
Sauer
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LA
Bassett Research Institute, Cooperstown, New York 13326, USA. lensauer@juno.com
Dauchy
R T
RT
Blask
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D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002100:Cachexia / Q000097:blood / Q000188:drug therapy*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D005227:Fatty Acids / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000493:pharmacokinetics*; D019204:GTP-Binding Proteins / Q000378:metabolism; D008041:Linoleic Acids / Q000096:biosynthesis; D008114:Liver Neoplasms, Experimental / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D009368:Neoplasm Transplantation; D051381:Rats; D011915:Rats, Inbred BUF; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013936:Thymidine / Q000378:metabolism; D017962:alpha-Linolenic Acid / Q000494:pharmacology*
D000970:Antineoplastic Agents; D005227:Fatty Acids; D008041:Linoleic Acids; D017962:alpha-Linolenic Acid; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; C024348:13-hydroxy-9,11-octadecadienoic acid; D015118:Eicosapentaenoic Acid; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D013936:Thymidine