A provisional mechanistic scheme by which the host circadian system regulates cancer metabolism by linking lipid signaling with the Warburg effect in human breast cancer xenografts via the nocturnal melatonin signal.

<p>During the light phase, host blood levels of linoleic acid are low and melatonin concentrations are nil; however, cAMP-stimulated tumor uptake of linoleic acid and its metabolism to the mitogenic signaling molecule 13-HODE is maximal. Increased production of 13-HODE stimulates increased levels and phosphorylation/activation of AKT leading to enhanced aerobic glycolysis, cell proliferation and tumor growth. The introduction of dim LAN induces the continued operation of the tumor growth stimulatory mechanisms observed during the light phase. During the dark phase, host blood levels of linoleic acid are high and melatonin concentrations are maximal. Melatonin, by acting through tumor MT₁ receptors <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0102776#pone.0102776-Blask2" target="_blank">[12]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0102776#pone.0102776-Blask3" target="_blank">[27]</a>, down-regulates cAMP formation and blocks linoleic acid uptake and its metabolism to 13-HODE. Decreased production of 13-HODE results in an attenuation of AKT signaling leading to diminished aerobic glycolysis, cell proliferation and tumor growth. Although the exact role of melatonin-induced HIF-1α expression during the dark phase is unclear, it may involve newly discovered transcription-independent mechanisms that paradoxically contribute to the inhibition of cell proliferation and cell survival <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0102776#pone.0102776-Xiang1" target="_blank">[32]</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0102776#pone.0102776-Hubbi1" target="_blank">[34]</a>.