The growth of rat
hepatoma 7288CTC in vivo is stimulated by the uptake of
linoleic acid (LA) and its metabolism to
13-hydroxyoctadecadienoic acid (13-HODE), an important mitogenic signaling molecule within this
tumor. Conversely, the growth of a variety of experimental
cancers in vivo is inhibited by either physiological or pharmacological levels of the pineal gland
hormone melatonin, although the mechanism(s) are unknown. We tested the hypothesis that the mechanism of
melatonin's anticancer action in vivo involves the inhibition of
tumor LA uptake and metabolism to
13-HODE in
hepatoma 7288CTC.
Tumor uptake of LA and release of
13-HODE, measured in tissue-isolated rat
hepatoma 7288CTC at 4-h intervals over a 24-h period, were highest during the light phase and lowest during the mid-dark phase, when plasma
melatonin levels were lowest and highest, respectively.
Pinealectomy eliminated this rhythm of
tumor LA uptake and
13-HODE production, indicating that it was driven by the circadian
melatonin rhythm. Perfusion of tissue-isolated
tumors in situ with
melatonin (1 nM) rapidly and reversibly inhibited the uptake of plasma
fatty acids (FAs), including LA, and its metabolism to
13-HODE. These inhibitory effects of
melatonin on
tumor FA uptake and
13-HODE release were completely reversed by perfusion of
tumors in situ with
melatonin receptor antagonist
S-20928,
pertussis toxin,
forskolin, or
8-bromo-cAMP. Perfusion of
tumors in situ with
melatonin also decreased
tumor [3H]
thymidine incorporation and
DNA content; these effects on
DNA synthesis were also prevented by the coperfusion of
tumors with
melatonin and
S-20928,
pertussis toxin,
forskolin, 8-Br-cAMP, or
13-HODE.
Pinealectomy stimulated
tumor growth, LA uptake and metabolism to
13-HODE, and FA storage in
hepatoma 7288CTC, whereas
melatonin administration (200 microg/day) was inhibitory in vivo. Northern blot analysis revealed that, compared with normal liver tissue,
hepatoma 7288CTC overexpressed
mRNA transcripts for a plasma membrane-associated FA
transport protein (FATP). FATP
mRNA expression was unaffected by the treatment of
tumor-bearing rats with daily afternoon
melatonin injections or exposure to constant light. These results support a novel mechanism of
tumor growth inhibition by
melatonin involving a
melatonin receptor-mediated suppression of cAMP levels, resulting in diminished
tumor FA transport, possibly via decreased FATP function. The inhibition of these signal transduction events by
melatonin culminates in the suppression of LA uptake, LA metabolism to the mitogenic signaling molecule
13-HODE, and
cancer growth.