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: 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
• Journal: Molecular endocrinology (Baltimore, Md.) (Mol Endocrinol) Vol. 26 Issue 11 Pg. 1808-20 (Nov 2012) ISSN: 1944-9917 [Electronic] United States
• PMID: 23002080 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Snai2 protein, rat
• Snail Family Transcription Factors
• Transcription Factors
• beta Catenin
• Phosphoserine
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, rat
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3
• Melatonin

Topics

• Animals
• Breast Neoplasms (enzymology, pathology, physiopathology)
• Cell Line, Tumor
• Circadian Rhythm (drug effects, radiation effects)
• Enzyme Activation (drug effects, radiation effects)
• Epithelial-Mesenchymal Transition (drug effects, radiation effects)
• Female
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Humans
• Light
• Male
• Melatonin (metabolism, pharmacology)
• Models, Biological
• Phosphorylation (drug effects, radiation effects)
• Phosphoserine (metabolism)
• Prostatic Neoplasms (enzymology, pathology, physiopathology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Snail Family Transcription Factors
• Transcription Factors (metabolism)
• Xenograft Model Antitumor Assays
• Young Adult
• beta Catenin (metabolism)