Abstract 165: The anticarcinogenic effects of melatonin on inhibition of fatty acid transport and 13-HODE production in HT29 human colorectal cancer occurs via receptor-mediated signal transduction

Abstract

Abstract Over 620,000 people in the U.S. alone this year will be diagnosed with either breast, prostate, or colorectal cancers, which represent nearly 50% of all reported malignancies. Patients with advanced stage breast, prostate, or colorectal cancer have only a 35% survival rate at 5 years. Epidemiological studies have indicated that the risk of these cancers is increased in persons exposed to excessive sunlight or, interestingly, ocular light at night, as experienced by night-shift workers. This latter finding was shown to be associated with a suppression of the nighttime production of the circadian neurohormone melatonin. Previous work from this laboratory using perfused, tissue-isolated human breast and prostate tumors showed that tumor growth and metabolism in vivo is dependent upon uptake of linoleic acid (LA), the most prominent fatty acid in our western diet, and its conversion to 13-hydroxyoctadecadienoic acid (13-HODE). In tissue-isolated human MCF-7 (steroid responsive and non-responsive) and PC3 prostate tumors perfused in situ with arterial blood, melatonin inhibits LA-uptake and conversion to 13-HODE, a lipoxygenase product that stimulates EGF mitogenesis. The present study explores the effects in vivo of melatonin (500 pM) on perfused, tissue isolated HT29 colorectal carcinomas in nude rats. HT29 colorectal carcinoma latency-to-onset and growth rates, respectively, of 12 days and 0.12 ± 0.01 g/day; mean tumor weights were 5.6 ± 0.2 g (n = 20). Colorectal carcinomas perfused in situ with donor rodent blood for 2 hours (Controls) revealed a tumor LA uptake and 13-HODE release of 0.86 ± 0.08 μg/min/g (20.0 ± 1.6% of arterial supply) and 3.23 ± 0.81 ng/min/g, respectively. Incorporation of 3H-thymidine into tumor DNA and DNA content, respectively were 25.9 ± 1.6 dpms/μg DNA and 2.7 ± 0.1 μg/g tumor. Carcinomas perfused with arterial donor blood augmented with physiological nocturnal levels of 500 pM melatonin showed a complete inhibition of LA uptake, 13-HODE release, ERK 1/2, MEK, Akt, and GSK3β activities, and over a 90% reduction in tumor cAMP levels and [3H]thymidine incorporation into tumor DNA. Addition of the non-selective MT1/MT2 melatonin antagonist S20928, forskolin, 8-Bromo-cyclic-AMP, or pertussis toxin completely reversed the tumor growth inhibitory response. Also, addition of 13-HODE reversed the inhibition of 3H-thymidine incorporation into tumor DNA, while having no effect on LA uptake. These results are the first to demonstrate in HT29 colorectal carcinoma that nocturnal melatonin levels suppress tumor growth via a melatonin receptor-mediated signal transduction mechanism. An understanding of this signaling pathway for the control of LA uptake in cancer could lead to new approaches for therapeutic intervention and/or chemoprevention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 165. doi:1538-7445.AM2012-165