The Molecular Circadian Clock Is a Target of Anti-cancer Translation Inhibitors

Area of Science:

• Molecular Biology
• Chronobiology
• Cardiovascular Physiology

Background:

• Circadian rhythms are fundamental to physiological homeostasis, regulating metabolic, immunologic, and cardiovascular functions.
• Core circadian clock components are transcription factors with precisely regulated half-lives, essential for cellular rhythmicity.
• Disruptions in molecular clock components can lead to significant pathologies affecting behavior and physiology.

Purpose of the Study:

• To identify novel modulators of the cardiomyocyte molecular clock.
• To investigate the effects of protein synthesis inhibitors on circadian clock components in cardiomyocytes.

Main Methods:

• Utilized a transcriptional signature similarity approach to identify potential clock modulators.
• Tested various eukaryotic protein translation inhibitors, including initiation and elongation inhibitors (e.g., rocaglates, 4-EGI1, homoharringtonine, puromycin).
• Assessed the impact of these inhibitors on the protein abundance of molecular clock components like REV-ERBα and PER2, both in vitro and in vivo.

Main Results:

• Identified anti-cancer protein synthesis inhibitors as potent modulators of the cardiomyocyte molecular clock.
• Demonstrated that protein translation inhibitors significantly reduce the protein levels of REV-ERBα, a key nuclear receptor and clock component.
• Observed similar inhibitory effects on PER2, another crucial component of the molecular clock, in both cellular and in vivo models.

Conclusions:

• Protein synthesis inhibitors can effectively modulate the cardiomyocyte molecular clock by altering the abundance of core clock proteins.
• The known clinical applications of protein synthesis inhibitors (cancers, viral infections) may need to be extended to include circadian rhythm disruption.
• Acute or prolonged administration of these inhibitors could have significant beneficial or detrimental effects on circadian rhythms.