title: Melatonin suppression of aerobic glycolysis (Warburg effect), survival signalling and metastasis in human leiomyosarcoma.
abstract: Leiomyosarcoma (LMS) represents a highly malignant, rare soft tissue sarcoma with high rates of morbidity and mortality. Previously, we demonstrated that tissue-isolated human LMS xenografts perfused in situ are highly sensitive to the direct anticancer effects of physiological nocturnal blood levels of melatonin which inhibited tumour cell proliferative activity, linoleic acid (LA) uptake and metabolism to 13-hydroxyoctadecadienoic acid (13-HODE). Here, we show the effects of low pharmacological blood concentrations of melatonin following oral ingestion of a melatonin supplement by healthy adult human female subjects on tumour proliferative activity, aerobic glycolysis (Warburg effect) and LA metabolic signalling in tissue-isolated LMS xenografts perfused in situ with this blood. Melatonin markedly suppressed aerobic glycolysis and induced a complete inhibition of tumour LA uptake, 13-HODE release, as well as significant reductions in tumour cAMP levels, DNA content and [(3) H]-thymidine incorporation into DNA. Furthermore, melatonin completely suppressed the phospho-activation of ERK 1/2, AKT, GSK3β and NF-kB (p65). The addition of S20928, a nonselective melatonin antagonist, reversed these melatonin inhibitory effects. Moreover, in in vitro cell culture studies, physiological concentrations of melatonin repressed cell proliferation and cell invasion. These results demonstrate that nocturnal melatonin directly inhibited tumour growth and invasion of human LMS via suppression of the Warburg effect, LA uptake and other related signalling mechanisms. An understanding of these novel signalling pathway(s) and their association with aerobic glycolysis and LA metabolism in human LMS may lead to new circadian-based therapies for the prevention and treatment of LMS and potentially other mesenchymally derived solid tumours.
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.|Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USA.|Tulane Center for Circadian Biology, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: Lulu
authors.initials: L
authors.lastname: Mao
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.|Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USA.|Tulane Center for Circadian Biology, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Dauchy
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.|Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USA.|Tulane Center for Circadian Biology, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Blask
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Dauchy
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Slakey
authors.affiliation: Department of Surgery, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Brimer
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.|Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USA.|Tulane Center for Circadian Biology, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.|Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USA.|Tulane Center for Circadian Biology, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: Shulin
authors.initials: S
authors.lastname: Xiang
authors.affiliation: Department of Surgery, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Hauch
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: Kara
authors.initials: K
authors.lastname: Smith
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.|Tulane Center for Circadian Biology, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: Tripp
authors.initials: T
authors.lastname: Frasch
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.|Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USA.|Tulane Center for Circadian Biology, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: Victoria P
authors.initials: VP
authors.lastname: Belancio
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.|Tulane Center for Circadian Biology, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Wren
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.|Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USA.|Tulane Center for Circadian Biology, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Hill
mesh_terms: D000818:Animals; D002470:Cell Survival; D005260:Female; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D007890:Leiomyosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008550:Melatonin / Q000378:metabolism*; D009362:Neoplasm Metastasis; D051381:Rats; D011923:Rats, Nude; D023041:Xenograft Model Antitumor Assays
chemical_list: D008550:Melatonin
keywords: Warburg effect; leiomyosarcoma; melatonin; metastasis; signalling pathways