Circadian Gating of Epithelial-to-mesenchymal Transition in Breast Cancer Cells Via Melatonin-regulation of GSK3β

Overview

Journal Mol Endocrinol

Specialties Endocrinology
Molecular Biology

Date 2012 Sep 25

PMID 23002080

Citations 45

Authors

Lulu Mao

Robert T Dauchy

David E Blask

Lauren M Slakey

Shulin Xiang

Lin Yuan

Erin M Dauchy

Bin Shan

George C Brainard

John P Hanifin

Tripp Frasch

Tamika T Duplessis

Steven M Hill

Affiliations

Soon will be listed here.

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.

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