Abstract 1324: Melatonin-depleted blood from healthy adult men exposed to environmental light at night stimulates growth, signal transduction and metabolic activity of tissue-isolated human prostate cancer xenografts in nude rats

Abstract

Abstract Light at night (LAN), via its ability to suppress nocturnal circadian pineal melatonin production, has been associated with an increased risk of prostate, breast, and endometrial cancers reported in rotating night shift workers. In previous studies, we determined that melatonin's tumor growth inhibitory mechanism occurs via an MT1 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). These events culminate in down-regulation of the epidermal growth factor and insulin-like growth factor-1 pathways. Tissue-isolated, androgen-independent PC3 human prostate tumor xenografts (n=3/group; 57 perfusions) perfused for 60 minutes in situ in male nude rats with melatonin-rich blood (> 100 pg/ml) collected from healthy adult, male subjects (n = 3) during the night were compared to those perfused with melatonin-deficient blood (< 10 pg/ml) collected during the daytime or nighttime following 90 minutes of ocular exposure to bright, white fluorescent light (2800 lux). Perfusion of tissue-isolated PC3 human prostate xenografts with human donor nighttime-collected, melatonin-rich blood samples resulted in substantial reductions (60 – 99%) in tumor cAMP levels, LA uptake, 13-HODE production, glucose uptake, O2 consumption and CO2 production, and [3H]thymidine incorporation into tumor DNA, compared to tumors perfused with daytime-collected or nighttime/light exposure-collected, melatonin-diminished blood samples. The activation of MEK, ERK 1/2, Akt, and glycogen synthase kinase-3β (GSK3β), was also markedly diminished in tumors perfused with melatonin-rich, nighttime-collected blood and stimulated in tumors perfused with melatonin-deficient blood collected after exposure to light at night. Tumor inhibitions by melatonin-rich blood were completely prevented by a non-selective MT1/MT2 melatonin receptor antagonist, forskolin, pertussis toxin, or 8-Bromo-cAMP. These results are the first to demonstrate that the nocturnal melatonin signal in blood collected from male human volunteers during the night suppresses signal transduction, metabolic and growth activity in tissue-isolated PC3 human prostate cancer xenografts via an MT1 melatonin receptor-mediated mechanism. These findings are also the first to show that blood collected from human subjects exposed to light at night markedly stimulates human prostate cancer growth, signal transduction and metabolic activity via suppression of the nocturnal circadian melatonin signal. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1324. doi:10.1158/1538-7445.AM2011-1324