Abstract 5167: Melatonin inhibition of linoleic acid transport and 13-HODE production in HeLa human cervical adenocarcinoma occurs via receptor-mediated signal transduction

Abstract

Abstract Over 12,000 women in the U.S. alone this year will be diagnosed with cervical cancer, ranking third behind endometrial and ovarian cancers. Patients with an advanced stage cervical cancer have only a 15-20% survival rate at 5 years. Observational studies of the night-shift worker population have shown an increased incidence of risk in persons exposed to ocular light at night in a number of cancers, including cervical cancer. This finding was associated with an inhibition of nighttime pineal gland production of melatonin, the circadian neurohormone shown to suppress tumor metabolic and proliferative activity. This occurs via melatonin inhibition of tumor linoleic acid (LA) uptake and conversion to 13-hydroxyoctadecadienoic acid (13-HODE), a molecule that upregulates epidermal growth factor and insulin-like growth factor-I-induced mitogenesis. Here, we investigate the effects in vivo of melatonin (500 pM) on perfused, tissue-isolated HeLa human adenocarcinoma xenografts in nude rats. HeLa adenocarcinoma latency-to-onset and tumor growth rates were, respectively, 8 days and 0.09 ± 0.01 g/day; mean tumor weights were 5.9 ± 0.3 g (n = 32). Cervical adenocarcinomas perfused in situ with donor rodent blood for 150 minutes (Controls) revealed a tumor glucose uptake and lactate release of 11.4 ± 0.9 ng/min/g and −20.4 ± 2.2 nmol/min/g, respectively; control tumor LA uptake and 13-HODE release was 0.71 ± 0.08 μg/min/g and 0.35 ± 0.07 ng/min/g, respectively. Incorporation of 3H-thymidine into tumor DNA and DNA content, respectively, were 21.2 ± 0.6 dpms/μg DNA and 2.5 ± 0.1 mg/g tumor. Adenocarcinomas perfused with arterial donor blood augmented with physiological nocturnal levels of 500 pM melatonin showed over a 20% abrogation of tumor glucose uptake and lactate production, O2 consumption and CO2 production, and a complete inhibition of LA uptake, 13-HODE release, ERK 1/2, MEK, Akt, GSK3β proliferative activities, and over an 85% reduction in tumor cAMP levels and 3H-thymidine incorporation into tumor DNA. Supplementation with the non-selective MT1/MT2 melatonin antagonist S20928, forskolin, 8-Bromo-cyclic-AMP, or pertusiss toxin completely reversed the tumor growth inhibitory response. Also, addition of 13-HODE reversed 3H-thymidine into tumor DNA, but had no effect on LA uptake. The preliminary results presented here demonstrate, for the first time, that nocturnal melatonin levels suppress HeLa cervical adenocarcinoma metabolism and proliferation in vivo via a melatonin receptor mediated signal transduction mechanism. A better understanding of this signaling pathway and the regulation of LA in cancer metabolism and proliferation may lead to new therapeutic and/or chemopreventative interventions. 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 5167. doi:1538-7445.AM2012-5167