Is our internal clock keeping cancer in check?

Our internal clock dictates sleeping patterns, appetite and body temperature, effectively setting the pace at which our bodies function. But what is its role in the treatment of cancer? Researchers from Charité – Universitätsmedizin Berlin have found that the body’s internal clock is capable of reducing the rate at which cells proliferate. Results from this study have been published in the journal PLOS Biology*.

Each cell in the human body has its own internal (or circadian) clock, which follows a 24-hour cycle. This clock regulates, among other things, metabolic processes and cell division. A master clock with overall control is housed in the brain; influenced by the transition between light and dark, it follows a day-night cycle. Permanent disruption of this internal clock can lead to a dysregulation of metabolic processes and cell division, resulting in the body becoming more susceptible to disease, including cancer.

Under the leadership of PD Dr. Angela Relógio (MKFZ-Molecular Cancer Research Center and Institute of Theoretical Biology), the researchers studied the interplay between clock and cell cycle components. They also studied the dysregulatory and hyperactive effects of a protein known as RAS, a mutated form of which is found in approximately a quarter of all cancer cases. In addition to this, the researchers focused on two other proteins, Ink4a and Arf, which are known to suppress cancer. They were able to show that RAS, which is responsible for cell proliferation, can impair the interplay between clock and cell cycle, and that this effect is mediated by the two proteins, Ink4a and Arf, which normally suppress cancer. Their results highlight the significance of the internal clock’s role in tumor suppression. “Findings from our cell model suggest that the clock is likely to act as a tumor suppressor, and that circumvent circadian control is advantageous to cancer cells,” explains Relógio, whose surname, by a happy coincidence, means ‘clock’ in Portuguese. She adds: “One cannot stop wondering whether disrupted circadian timing should be included as one of the hallmarks of cancer.” 

As a next step, the researchers will focus their efforts on comprehensive studies involving cell-based models. As part of these studies, the researchers will simulate treatment with various chemotherapy drugs, in order to further explore the effects our biological clock can have on treatment. The researchers’ findings confirm and support the results of previously published chronotherapy research, and underscore the significance of our biological clock. To optimize outcomes, treatment regimens should be reviewed to take account of the patient's internal clock.

*Rukeia El-Athman, Nikolai N. Genov, Jeannine Mazuch, Kaiyang Zhang, Yong Yu, Luise Fuhr, Mónica Abreu, Yin Li, Thomas Wallach, Achim Kramer, Clemens A. Schmitt, Angela Relógio. The Ink4a/Arf locus operates as a regulator of the circadian clock modulating RAS activity. Plos Biology. 2017 Dec. doi: 10.1371/journal.pbio.2002940.

Contact

PD Dr. Angela Relógio 
MKFZ - Molecular Cancer Research Center and Institute of Theoretical Biology 
Charité – Universitätsmedizin Berlin         
Tel: + 49 30 2093 6044