The Interplay of Circadian Rhythms, Biological Clocks, and Cancer Pathogenesis

Cancer Research Group (CRG), Universidad de Las Américas, Quito, Ecuador.
The Interplay of Circadian Rhythms, Biological Clocks, and Cancer Pathogenesis
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This Behind of Paper delves into the intricate relationship between circadian rhythm (CR) disruption and cancer pathogenesis1. CRs are fundamental biological processes, lasting about 24 hours, that regulate essential physiological and behavioral functions. These include sleep-wake cycles, cellular activities, mitochondrial functions, DNA repair mechanisms, hypoxia, autophagy, apoptosis, and immune responses2. Central to these rhythms are the biological clocks, predominantly located in the suprachiasmatic nucleus (SCN) but also dispersed peripherally across body cells. Guided by external cues, or zeitgebers, such as light and temperature, these clocks fine-tune our CRs3. The pivotal question remains: What makes this delicate interplay of CRs so crucial, and how does it connect with health concerns like cancer?

The genes and proteins that fuel these rhythms function within a rhythmic feedback loop mechanism. The SCN, as the central pacemaker, governs the peripheral clocks in nearly every cell of our body. Interestingly, these peripheral clocks can recalibrate autonomously based on environmental signals, forming a feedback system that ensures CRs are synchronized throughout the body. Interruptions in this system, whether from prolonged exposure to electric light at night, sleep deprivation, night shift work, chronic jet lag, or nocturnal eating habits, are closely associated with impaired neurocognitive development, mental disorders, cardiovascular diseases, metabolic diseases, and cancer4. In particular, alterations in CRs can influence the behavior of genes tied to tumor development, thus increasing cancer vulnerabilities.

Recent advancements in chronobiology have shed light on the significant impact rhythm disturbances have on cancer development5. When these rhythms go awry, they affect numerous cellular processes essential for health, like cellular growth, inflammation, apoptosis regulation, and even our body's reaction to anti-cancer drugs6. Such disturbances can inadvertently create an environment conducive for cancer onset and its subsequent progression. Notably, certain proteins governed by the circadian clock are instrumental in cellular functions. Any disruption to these proteins can lead to significant hallmarks of cancer7.

The innovative concept of "drugging the clock" offers a fresh perspective on cancer treatment. By targeting the circadian clock and its associated pathways, we might unlock a more precise and potent cancer therapeutic approach3. Recent multi-omics analyses have pinpointed several CR-associated genes and proteins with a notable correlation to cancer. Some of these genes and proteins represent promising therapeutic targets, with drugs aimed at them currently in clinical trials. Proteins such as CSNK1D and CSNK1E, essential for circadian rhythm regulation, and others like CDK1 and TP53, are being studied for their therapeutic potential1. Moreover, the phenomenon of metastasis, a defining feature of aggressive cancers, has a connection with circadian rhythm disturbances. Understanding these links and the potential of CR-related proteins in cancer prognosis and treatment can pave the way for enhanced pharmacogenomic strategies, potentially revolutionizing cancer treatment.

In summary, our study  uncovers a pioneering therapeutic landscape anchored in the concept of "drugging the clock." This strategy, focusing on the circadian clock's potential for cancer management, underscores the promising merger of circadian biology and oncology. This fusion, amplified by pharmacogenomic insights, personalized clinical data, and ethnic considerations, not only elevates the accuracy, customization, and efficacy of cancer treatments, but also reduces adverse effects. Yet, due to the emergent nature of this domain, thorough research and rigorous clinical evaluations remain essential to ascertain the efficacy and safety of these interventions1.

 

References

  1. Pérez-Villa, A., et al. Integrated multi-omics analysis reveals the molecular interplay between circadian clocks and cancer pathogenesis. Sci Rep. 13, 14198 (2023).
  2. Logan, R. W. & McClung, C. A. Rhythms of life: Circadian disruption and brain disorders across the lifespan. Rev. Neurosci. 20, 49–65 (2019).
  3. Sulli, G., et al. Interplay between circadian clock and cancer: New frontiers for cancer treatment. Trends Cancer 5, 475–494 (2019).
  4. Yang, F. N., et al. Effects of sleep duration on neurocognitive development in early adolescents in the USA: A propensity score matched, longitudinal, observational study. Lancet Child Adolesc. Health 6, 705–712 (2022).
  5. Battaglin, F. et al. Clocking cancer: The circadian clock as a target in cancer therapy. Oncogene 40, 3187–3200 (2021).
  6. Lee, Y. Roles of circadian clocks in cancer pathogenesis and treatment. Mol. Med. 53, 1529–1538 (2021).
  7. Hanahan, D. Hallmarks of cancer: New dimensions. Cancer Discov. 12, 31–46 (2022).

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