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In the United States alone this year approximately 3,500 people will be diagnosed with leiomyosarcoma (LMS), a rare, malignant soft tissue cancer derived from smooth muscle cells, and about 36% will perish from this disease, despite the current medical interventions of surgery, radio- and chemotherapy. Epidemiological studies have indicated that the risk of many types of epithelial cancer including breast, prostate, colorectal, and endometrial cancer is increased in night-shift workers. These individuals experience circadian disruption in response to ocular exposure to light at night, which suppresses the nocturnal circadian production of melatonin by the pineal gland. In previous studies, we demonstrated that human LMS perfused with rodent donor blood containing physiological nocturnal levels of melatonin (1nM) showed a complete inhibition of LA uptake, 13-HODE release, and marked reduction in tumor cAMP levels and [3H]thymidine incorporation into tumor DNA. Here we showed the in vivo effects of a physiological, nocturnal concentration of melatonin on tumor proliferative activity mediated via aerobic glycolysis (Warburg effect) and LA metabolic signaling in tissue-isolated LMS xenografts perfused in situ in nude rats with human donor blood. Following tumor implantation, LMS xenografts exhibited latency-to-onset and growth rates that were 22 days and 0.21 ± 0.04 g/day, respectively; mean tumor weights were 5.1 ± 0.2 g (n = 72). The tissue-isolated human LMS xenografts in nude rats perfused in situ for 60 min with human donor blood containing melatonin resulted in a significant reduction in tumor aerobic glycolysis that included a 30-50% reduction in glucose uptake, lactate release, O2 uptake and CO2 production. Additionally, melatonin induced a complete inhibition of LA uptake, 13-HODE release, ERK 1/2, Akt, GSK3β (Ser9), and NF-kB (p65) phosphorylation, as well as significant reductions in tumor cAMP levels, DNA content and [3H]thymidine incorporation into tumor DNA. Addition of the non-selective MT1/MT2 melatonin antagonist S20928 (1 μM) completely reversed the inhibitory effects of melatonin on aerobic glycolysis, LA metabolic signaling and proliferative activity in LMS xenografts. Moreover, melatonin at physiological concentrations (1 nM) induced a 30-50% inhibition in cell proliferation in culture, and suppressed cell invasion by 30% in the transwell assay. These results demonstrate that in human LMS nocturnal melatonin levels directly and rapidly inhibit tumor growth activity and invasion via suppression of the Warburg effect and LA metabolic and other related signaling mechanisms. An understanding of this novel signaling pathway for the control of aerobic glycolysis and LA metabolism in human leiomyosarcoma could lead to new circadian-based approaches for cancer therapy and/or prevention of rare but highly aggressive mesenchymally-derived solid tumors. Citation Format: Lulu Mao, Robert T. Dauchy, Erin M. Dauchy, Melissa A. Wren, Samantha D. Zeringue, Victoria P. Belancio, David E. Blask, Steven M. Hill. Melatonin inhibits aerobic glycolysis (Warburg effect) and fatty acid metabolic signaling in human leiomyosarcoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5423. doi:10.1158/1538-7445.AM2013-5423 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.