期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 6, 页码 -出版社
MDPI
DOI: 10.3390/ijms22062974
关键词
circadian rhythm; period; p53; chronotherapy
资金
- Fondazione Umberto Veronesi
- project Ritmo circadiano e infezioni: studio della regolazione circadiana di virulenza e metabolismo nei funghi, Fondo Ricerca di Base, University of Perugia
- Associazione Umbra Contro il Cancro (AUCC)
- Fondazione Cassa di Risparmio di Perugia
- PRIN 2015 Project [20152CB22L_004]
The circadian clock regulates fundamental physiological processes and can impact the response to anticancer treatments, but the molecular mechanisms linking circadian rhythms to anticancer actions are still poorly understood, limiting the application of chronotherapy in clinical practice.
The circadian clock driven by the daily light-dark and temperature cycles of the environment regulates fundamental physiological processes and perturbations of these sophisticated mechanisms may result in pathological conditions, including cancer. While experimental evidence is building up to unravel the link between circadian rhythms and tumorigenesis, it is becoming increasingly apparent that the response to antitumor agents is similarly dependent on the circadian clock, given the dependence of each drug on the circadian regulation of cell cycle, DNA repair and apoptosis. However, the molecular mechanisms that link the circadian machinery to the action of anticancer treatments is still poorly understood, thus limiting the application of circadian rhythms-driven pharmacological therapy, or chronotherapy, in the clinical practice. Herein, we demonstrate the circadian protein period 1 (PER1) and the tumor suppressor p53 negatively cross-regulate each other's expression and activity to modulate the sensitivity of cancer cells to anticancer treatments. Specifically, PER1 physically interacts with p53 to reduce its stability and impair its transcriptional activity, while p53 represses the transcription of PER1. Functionally, we could show that PER1 reduced the sensitivity of cancer cells to drug-induced apoptosis, both in vitro and in vivo in NOD scid gamma (NSG) mice xenotransplanted with a lung cancer cell line. Therefore, our results emphasize the importance of understanding the relationship between the circadian clock and tumor regulatory proteins as the basis for the future development of cancer chronotherapy.
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