Abstract 4001: The circadian neurohormone melatonin inhibits aerobic glycolysis (Warburg effect) and fatty acid metabolic signaling in human colorectal and cervical cancer.

Over 630,000 people in the U.S. alone this year will be diagnosed with either breast, prostate, colorectal, or cervical cancers. Epidemiological studies have indicated that the risk of breast, prostate and colorectal 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 determined that nocturnal blood levels of melatonin inhibit tissue-isolated human breast cancer xenograft growth via suppression of an MT 1 melatonin receptor-mediated suppression of tumor cAMP leading to an inhibition of tumor linoleic acid (LA) uptake and its metabolism to the mitogenic signaling molecule 13-hydroxyoctadecadienoic acid (13-HODE), culminating in down-regulation of the epidermal growth factor and insulin-like growth factor-1 signaling pathways. Here we showed the effects in vivo of a physiological, nocturnal concentration of melatonin (500 pM) on tumor proliferative activity mediated via aerobic glycolysis (Warburg effect) and LA metabolic signaling in tissue-isolated human HT-29 colorectal and HeLa cervical cancer xenografts perfused in situ in nude rats. Following tumor implantation, HT29 colorectal and HeLa cervical cancer xenografts exhibited latency-to-onset and growth rates that were 12 and 8 days, and 0.12 ± 0.01 and 0.09 ± 0.01 g/day, respectively; mean tumor weights were 5.6 ± 0.2 g (n = 20/group). These tissue-isolated human cancer xenografts in nude rats perfused in situ for 60 min with rat donor blood containing melatonin resulted in a significant reduction in tumor aerobic glycolysis that included a 30% reduction in glucose uptake, lactate release, O 2 uptake and CO 2 production. Additionally, melatonin induced a complete inhibition of LA uptake, 13-HODE release, ERK 1/2, MEK, Akt, and GSK3β expression, as well as significant reductions in tumor cAMP levels, DNA content and [ 3 H]thymidine incorporation into tumor DNA. Addition of the non-selective MT 1 /MT 2 melatonin antagonist S20928, forskolin, 8-Bromo-cyclic-AMP, or pertussis toxin to the tumor perfusate completely reversed the inhibitory effects of melatonin on aerobic glycolysis, LA metabolic signaling and proliferative activity in both types of xenografts. These results demonstrate in HT29 colorectal and HeLa cervical adenocarcinomas that nocturnal melatonin levels directly and rapidly inhibit tumor growth activity via a melatonin receptor-mediated 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 cancer could lead to new circadian-based approaches for cancer therapy and/or prevention. Citation Format: Robert T. Dauchy, Erin M. Dauchy, Lulu Mao, Melissa A. Wren, Victoria P. Belancio, Steven M. Hill, David E. Blask. The circadian neurohormone melatonin inhibits aerobic glycolysis (Warburg effect) and fatty acid metabolic signaling in human colorectal and cervical cancer. [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 4001. doi:10.1158/1538-7445.AM2013-4001