Abstract
BackgroundCircadian clocks control cell cycle factors, and circadian disruption promotes cancer. To address whether enhancing circadian rhythmicity in tumor cells affects cell cycle progression and reduces proliferation, we compared growth and cell cycle events of B16 melanoma cells and tumors with either a functional or dysfunctional clock.ResultsWe found that clock genes were suppressed in B16 cells and tumors, but treatments inducing circadian rhythmicity, such as dexamethasone, forskolin and heat shock, triggered rhythmic clock and cell cycle gene expression, which resulted in fewer cells in S phase and more in G1 phase. Accordingly, B16 proliferation in vitro and tumor growth in vivo was slowed down. Similar effects were observed in human colon carcinoma HCT-116 cells. Notably, the effects of dexamethasone were not due to an increase in apoptosis nor to an enhancement of immune cell recruitment to the tumor. Knocking down the essential clock gene Bmal1 in B16 tumors prevented the effects of dexamethasone on tumor growth and cell cycle events.ConclusionsHere we demonstrated that the effects of dexamethasone on cell cycle and tumor growth are mediated by the tumor-intrinsic circadian clock. Thus, our work reveals that enhancing circadian clock function might represent a novel strategy to control cancer progression.
Highlights
Circadian clocks control cell cycle factors, and circadian disruption promotes cancer
To further assess the specificity of the response, clock gene expression in the liver - a non-cancerous, peripheral tissue - was compared between phosphate-buffered saline (PBS)- and DEXinjected mice: we found no significant differences between the treatment groups (Additional file 5F)
Dexamethasone treatment slows down B16 tumor growth Given that activation of the circadian clock in B16 tumors triggered rhythms of cell cycle genes and phases, we evaluated whether the activation of clock function in B16 tumors was paralleled by a reduction in tumor growth
Summary
Circadian clocks control cell cycle factors, and circadian disruption promotes cancer. Tumor cells are characterized by uncontrolled cell proliferation resulting in abnormal and accelerated tissue growth. “healthy” cells often proliferate with a division rate of ~24 h [1]. This is due to the direct control of cell cycle checkpoints by the intracellular circadian clock machinery [2]. These clocks are based on clock genes, which participate in auto-regulatory feedback loops. The transcription factors CLOCK and BMAL1 activate the expression of Per and Cry genes, whose protein products negatively feed back on their own expression [4]. In any given cell type, 5–20% of the transcriptome is under
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