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Oncogenic and Circadian Effects of Small Molecules Directly and Indirectly Targeting the Core Circadian Clock

Hui-Hsien Lin1, Kelly L Robertson1, Heather A Bisbee1

  • 1University of Massachusetts Amherst, Amherst, MA, USA.

Integrative Cancer Therapies
|June 5, 2020
PubMed

Insights

Small molecules alter circadian rhythms in human cells, impacting cell behavior like motility and colony formation. The degree of circadian disruption, not just period length, significantly influences cellular outcomes, irrespective of the molecule

Area of Science:

  • * Molecular Biology
  • * Chronobiology
  • * Cancer Cell Biology

Background:

  • * Circadian rhythms regulate fundamental cellular processes including cell cycle, proliferation, and apoptosis, thereby influencing cell fate.
  • * Previous studies modulated circadian oscillations with small molecules but lacked comprehensive assessment of cellular effects or standardized comparisons.
  • * Understanding the interplay between circadian clock modulation and cellular behavior is crucial for therapeutic development.

Purpose of the Study:

  • * To investigate the effects of five small molecules, categorized as direct or indirect circadian clock effectors, on circadian oscillations in U2OS cells.
  • * To evaluate the influence of these modulations on cellular behaviors such as motility and colony formation.
  • * To determine if the mechanism of action (direct vs. indirect) or the extent of circadian disruption correlates with observed cellular effects.

Main Methods:

  • * Utilized human osteosarcoma (U2OS) cell line to model cellular responses.
  • * Employed luciferase reporter systems driven by *Bmal1* and *Per2* promoters for quantitative analysis of circadian rhythmicity.
  • * Assessed cell motility and colony formation assays to measure cellular behaviors.
  • * Administered five distinct small molecules to modulate circadian periods in a dose-dependent manner.

Main Results:

  • * All tested molecules modulated *Bmal1* and *Per2* circadian periods in a dose-dependent manner, either increasing or decreasing oscillation length.
  • * No direct correlation was found between circadian period length and the extent of cell migration or proliferation.
  • * Molecules causing greater disruption to circadian oscillations exhibited more significant impacts on cellular behaviors, potentially due to off-target effects.
  • * The efficacy of molecules in altering circadian oscillations was independent of whether they acted as direct or indirect modulators.

Conclusions:

  • * Small molecule-induced circadian rhythm disruption significantly influences cellular behaviors like motility and colony formation in U2OS cells.
  • * The extent of circadian modulation, rather than solely the period length, is a key factor in determining cellular responses.
  • * Non-circadian targets of these molecules likely contribute to the observed cellular effects.
  • * Given the intricate feedback loops between the circadian clock and other cellular pathways, comprehensive assessment of both direct and indirect effects is essential when evaluating compounds.
Keywords:
U2OS cellscell migrationcell proliferationcircadian rhythmclock periodluminescent reporterssmall molecule modulatorstumor growth

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