title: Circadian gating of epithelial-to-mesenchymal transition in breast cancer cells via melatonin-regulation of GSK3β.
abstract: Disturbed sleep-wake cycle and circadian rhythmicity are associated with cancer, but the underlying mechanisms are unknown. Employing a tissue-isolated human breast xenograft tumor nude rat model, we observed that glycogen synthase kinase 3β (GSK3β), an enzyme critical in metabolism and cell proliferation/survival, exhibits a circadian rhythm of phosphorylation in human breast tumors. Exposure to light-at-night suppresses the nocturnal pineal melatonin synthesis, disrupting the circadian rhythm of GSK3β phosphorylation. Melatonin activates GSK3β by inhibiting the serine-threonine kinase Akt phosphorylation, inducing β-catenin degradation and inhibiting epithelial-to-mesenchymal transition, a fundamental process underlying cancer metastasis. Thus, chronic circadian disruption by light-at-night via occupational exposure or age-related sleep disturbances may contribute to cancer incidence and the metastatic spread of breast cancer by inhibiting GSK3β activity and driving epithelial-to-mesenchymal transition in breast cancer patients.
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
authors.forename: Lulu
authors.initials: L
authors.lastname: Mao
authors.forename: Robert T
authors.initials: RT
authors.lastname: Dauchy
authors.forename: David E
authors.initials: DE
authors.lastname: Blask
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Slakey
authors.forename: Shulin
authors.initials: S
authors.lastname: Xiang
authors.forename: Lin
authors.initials: L
authors.lastname: Yuan
authors.forename: Erin M
authors.initials: EM
authors.lastname: Dauchy
authors.forename: Bin
authors.initials: B
authors.lastname: Shan
authors.forename: George C
authors.initials: GC
authors.lastname: Brainard
authors.forename: John P
authors.initials: JP
authors.lastname: Hanifin
authors.forename: Tripp
authors.initials: T
authors.lastname: Frasch
authors.forename: Tamika T
authors.initials: TT
authors.lastname: Duplessis
authors.forename: Steven M
authors.initials: SM
authors.lastname: Hill
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D045744:Cell Line, Tumor; D002940:Circadian Rhythm / Q000187:drug effects / Q000528:radiation effects; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008027:Light; D008297:Male; D008550:Melatonin / Q000378:metabolism* / Q000494:pharmacology; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D010768:Phosphoserine / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult; D051176:beta Catenin / Q000378:metabolism
chemical_list: C000604450:Snai2 protein, rat; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051176:beta Catenin; D010768:Phosphoserine; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D008550:Melatonin