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.