Dietary intake of the n-6 fatty acid (FA) linoleic acid (LA) has a strong g
rowth-promoting effect on many rodent tumors and human tumor xenografts gro
wn in immunodeficient rodents. n-3 FAs such as alpha-linolenic and eicosape
ntaenoic acids (EPAs), which differ from LA and arachidonic acid, respectiv
ely, by only a single double bond in the n-3 position, are recognized cance
r chemopreventive and anticachectic agents. Understanding how this seemingl
y small structural difference leads to such remarkable functional differenc
es has been a challenge. In a previous study, we showed that LA uptake, [H-
3]thymidine incorporation into DNA, and total DNA content were decreased in
tissue-isolated hepatoma 7288CTC perfused ill situ with arterial blood con
taining alpha-linolenic acid, EPA, or docosahexaenoic acids. The K-i for th
e inhibition of LA uptake and [H-3]thymidine incorporation by alpha-linolen
ic 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-hydroxy
octadecadienoic acid (13-HODE) in vivo and during perfusion in situ, [H-3]T
hymidine incorporation during perfusion in situ was also inhibited. Additio
n of 13-MODE to the arterial blood reversed the inhibition of [H-3]thymidin
e incorporation but had no effect on FA uptake, These two n-3 FAs also inhi
bited FA transport in inguinal fat pads in vivo and during perfusion in sit
u in fed QA uptake) and fasted (FA release) rats. The effects of EPA and al
pha-linolenic acid on transport of saturated, monounsaturated, and n-6 poly
unsaturated FAs in hepatoma 7288CTC and inguinal fat pads during perfusion
in situ were reversed by the addition of forskolin (1 mu M), pertussis toxi
n (0.5 mu g/ml), or 8-bromo-cyclic AMP (10 mu M) to the arterial blood. We
conclude that the antitumor and anticachectic effects of n-3 FAs on hepatom
a 7288CTC and inguinal fat pads in vivo result from an inhibition of FA tra
nsport. These inhibitions are mediated by a putative n-3 FA receptor via a
G(i) protein-coupled signal transduction pathway that decreases intracellul
ar cyclic AMP. A specific decrease in LA uptake and its conversion to the m
itogen 13-HODE causes the tumor growth inhibition.