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Enhancing circadian clock function in cancer cells inhibits tumor growth
Silke Kiessling1,2,3, Lou Beaulieu-Laroche1, Ian D Blum1
1Douglas Mental Health University Institute, Montreal, QC, H4H 1R3, Canada.
Background:
Circadian 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.
Results:
We 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.
Conclusions:
Here 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.
Insights
Enhancing circadian rhythmicity in tumor cells slows cancer progression. Treatments that boost the tumor
Area of Science:
- Chronobiology
- Cancer Biology
- Cell Cycle Regulation
Background:
- Circadian clocks regulate cell cycle factors.
- Disruption of circadian rhythms is linked to cancer development.
- Investigating the impact of enhanced circadian rhythmicity on tumor cells is crucial.
Purpose of the Study:
- To determine if enhancing circadian rhythmicity in tumor cells affects cell cycle progression.
- To assess the impact of circadian rhythmicity on tumor cell proliferation.
- To explore novel cancer control strategies targeting circadian clocks.
Main Methods:
- Comparison of B16 melanoma cells and tumors with functional or dysfunctional clocks.
- Treatment of cells and tumors with agents like dexamethasone, forskolin, and heat shock to induce circadian rhythmicity.
- Analysis of gene expression for clock and cell cycle factors.
- Assessment of cell cycle phase distribution (G1, S phase).
- Evaluation of tumor growth in vitro and in vivo.
- Knockdown of the Bmal1 gene in B16 tumors.
Main Results:
- Clock gene suppression was observed in B16 cells and tumors.
- Treatments induced rhythmic clock and cell cycle gene expression.
- Cells showed a shift from S phase to G1 phase.
- Proliferation and tumor growth were significantly reduced.
- Dexamethasone's effects were independent of apoptosis or immune cell recruitment.
- Bmal1 knockdown abolished the effects of dexamethasone.
Conclusions:
- The effects of dexamethasone on cell cycle and tumor growth are mediated by the tumor-intrinsic circadian clock.
- Enhancing circadian clock function presents a potential novel strategy for cancer progression control.
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