Dataset Information

Circadian gating of epithelial-to-mesenchymal transition in breast cancer cells via melatonin-regulation of GSK3?.

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 3? (GSK3?), 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 GSK3? phosphorylation. Melatonin activates GSK3? by inhibiting the serine-threonine kinase Akt phosphorylation, inducing ?-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 GSK3? activity and driving epithelial-to-mesenchymal transition in breast cancer patients.

SUBMITTER: Mao L

PROVIDER: S-EPMC3487627 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Publications

Circadian gating of epithelial-to-mesenchymal transition in breast cancer cells via melatonin-regulation of GSK3β.

Mao Lulu L Dauchy Robert T RT Blask David E DE Slakey Lauren M LM Xiang Shulin S Yuan Lin L Dauchy Erin M EM Shan Bin B Brainard George C GC Hanifin John P JP Frasch Tripp T Duplessis Tamika T TT Hill Steven M SM

Molecular endocrinology (Baltimore, Md.) 20120921 11

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 ...[more]

PMID: 23002080

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Project description:Perturbations in the adipocytokine profile, especially higher levels of leptin, are a major cause of breast tumor progression and metastasis; the underlying mechanisms, however, are not well understood. In particular, it remains elusive whether leptin is involved in epithelial-mesenchymal transition (EMT). Here, we provide molecular evidence that leptin induces breast cancer cells to undergo a transition from epithelial to spindle-like mesenchymal morphology. Investigating the downstream mediator(s) that may direct leptin-induced EMT, we found functional interactions between leptin, metastasis-associated protein 1 (MTA1), and Wnt1 signaling components. Leptin increases accumulation and nuclear translocation of ?-catenin leading to increased promoter recruitment. Silencing of ?-catenin or treatment with the small molecule inhibitor, ICG-001, inhibits leptin-induced EMT, invasion, and tumorsphere formation. Mechanistically, leptin stimulates phosphorylation of glycogen synthase kinase 3? (GSK3?) via Akt activation resulting in a substantial decrease in the formation of the GSK3?-LKB1-Axin complex that leads to increased accumulation of ?-catenin. Leptin treatment also increases Wnt1 expression that contributes to GSK3? phosphorylation. Inhibition of Wnt1 abrogates leptin-stimulated GSK3? phosphorylation. We also discovered that leptin increases the expression of an important modifier of Wnt1 signaling, MTA1, which is integral to leptin-mediated regulation of the Wnt/?-catenin pathway as silencing of MTA1 inhibits leptin-induced Wnt1 expression, GSK3? phosphorylation, and ?-catenin activation. Furthermore, analysis of leptin-treated breast tumors shows increased expression of Wnt1, pGSK3?, and vimentin along with higher nuclear accumulation of ?-catenin and reduced E-cadherin expression providing in vivo evidence for a previously unrecognized cross-talk between leptin and MTA1/Wnt signaling in epithelial-mesenchymal transition of breast cancer cells.

Dataset Information

Circadian gating of epithelial-to-mesenchymal transition in breast cancer cells via melatonin-regulation of GSK3?.

Publications

Circadian gating of epithelial-to-mesenchymal transition in breast cancer cells via melatonin-regulation of GSK3β.

Similar Datasets

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