The Circadian Protein PER1 Modulates the Cellular Response to Anticancer Treatments.

Marina Maria Bellet,Claudio Costantini,Luigina Romani,Claudia Stincardini,Danilo Piobbico,Paolo Sassone-Corsi,Marco Gargaro,Maria Agnese Della-Fazia,Giuseppe Servillo,Stefania Pieroni,Marilena Castelli

doi:10.3390/ijms22062974

Marina Maria Bellet, Claudio Costantini + Show 9 more

Open Access

https://doi.org/10.3390/ijms22062974

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Abstract

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.

Highlights

Organisms have evolved to adapt their behavior and physiology to the daily light-dark and temperature cycles of the environment
In order to study the relationship between p53 and PER1 in the context of cellular response to chemotherapeutic drugs, we stably overexpressed PER1 (PER1) or a control plasmid (CTRL) in the p53-sufficient human cancer A549 cells (Figure 1A)
Using a synthetic reporter vector carrying p53 responsive elements (p53-RE) fused to the luciferase gene, we demonstrated that PER1 overexpression was able to induce a modest but significant repression of the transactivation of p53-RE mediated by p53 (Figure 1J)

Summary

Introduction

Organisms have evolved to adapt their behavior and physiology to the daily light-dark and temperature cycles of the environment. This circadian rhythmicity is guaranteed by the presence of circadian clocks, collectively indicating central and peripheral endogenous systems that synchronize the organismal physiology to the environmental changes and optimize overall fitness [1]. The PER/CRY protein complexes inactivate CLOCK/BMAL1 (C/B), closing the circuit [2]. Disruption of these finetuning processes may reduce the fitness of the organism and increase the susceptibility to the development of pathological conditions, including cancer [3]. The circadian rhythms influence the process of tumorigenesis, and the response of the tumor to therapeutic agents, with a view to a personalized medicine driven by circadian rhythms, or chronotherapy

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