Melatonin inhibition of cancer growth in vivo involves suppression of tumor fatty acid metabolism via melatonin receptor-mediated signal transductionevents

The growth of rat hepatoma 7288CTC in vivo is stimulated by the uptake of I inoleic acid (LA) and its metabolism to 13-hydroxyoctadecadienoic acid (13- HODE), an important mitogenic signaling molecule within this tumor. Convers ely, the growth of a variety of experimental cancers ill vivo is inhibited by either physiological or pharmacological levels of the pineal gland hormo ne melatonin, although the mechanism(s) are unknown. We tested the hypothes is that the mechanism of melatonin's anticancer action in vivo involves the inhibition of tumor LA uptake and metabolism to 13-HODE in hepatoma 7288CT C, Tumor uptake of LA and release of 13-HODE, measured in tissue-isolated r at hepatoma 7288CTC at 4-h intervals over a 24-h period, were highest durin g the light phase and lowest during the mid-dark phase, when plasma melaton in levels were lowest and highest, respectively. Pinealectomy eliminated th is rhythm of tumor LA uptake and 13-HODE production, indicating that it was driven by the circadian melatonin rhythm. Perfusion of tissue-isolated tum ors in situ with melatonin (1 nM) rapidly and reversibly inhibited the upta ke 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 rele ase were completely reversed by perfusion of tumors in situ with melatonin receptor antagonist S-20928, pertussis toxin, forskolin, or 8-bromo-cAMP. P erfusion of tumors in situ with melatonin also decreased tumor [H-3]thymidi ne incorporation and DNA content; these effects on DNA synthesis were also prevented by the coperfusion of tumors with melatonin and S-20928, pertussi s toxin, forskolin, 8-Br-cAMP, or 13-HODE. Pinealectomy stimulated tumor gr owth, LA uptake and metabolism to 13-HODE, and PA storage in hepatoma 7288C TC, whereas melatonin administration (200 mu g/day) was inhibitory in vivo, Northern blot analysis revealed that, compared with normal liver tissue, h epatoma 7288CTC overexpressed mRNA transcripts for a plasma membrane-associ ated FA transport protein (FATP), FATP mRNA expression was unaffected by th e 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-mediate d suppression of cAMP levels, resulting in diminished tumor FA transport, p ossibly via decreased FATP function. The inhibition of these signal transdu ction events by melatonin culminates in the suppression of LA uptake, LA me tabolism to the mitogenic signaling molecule 13-HODE, and cancer growth.