The Circadian Protein PER1 Modulates the Cellular Response to Anticancer Treatments.
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.
['Bellet|Marina Maria|MM|', 'Stincardini|Claudia|C|', 'Costantini|Claudio|C|0000-0002-1433-7830', 'Gargaro|Marco|M|0000-0003-0645-9800', 'Pieroni|Stefania|S|', 'Castelli|Marilena|M|', 'Piobbico|Danilo|D|0000-0003-4240-1526', 'Sassone-Corsi|Paolo|P|', 'Della-Fazia|Maria Agnese|MA|', 'Romani|Luigina|L|', 'Servillo|Giuseppe|G|0000-0001-7960-7689']
D000072283:A549 Cells D000818:Animals D000970:Antineoplastic Agents D017209:Apoptosis D063646:Carcinogenesis D002453:Cell Cycle D045744:Cell Line, Tumor D002940:Circadian Rhythm D002945:Cisplatin D000077143:Docetaxel D055870:Drug Chronotherapy D005047:Etoposide D006801:Humans D051379:Mice D009369:Neoplasms D056950:Period Circadian Proteins D016159:Tumor Suppressor Protein p53 D023041:Xenograft Model Antitumor Assays
circadian rhythm chronotherapy period p53