The Relationship between Circadian Rhythm and Cancer Disease

Abstract

The circadian clock regulates biological cycles across species and is crucial for physiological activities and biochemical reactions, including cancer onset and development. The interplay between the circadian rhythm and cancer involves regulating cell division, DNA repair, immune function, hormonal balance, and the potential for chronotherapy. This highlights the importance of maintaining a healthy circadian rhythm for cancer prevention and treatment. This article investigates the complex relationship between the circadian rhythm and cancer, exploring how disruptions to the internal clock may contribute to tumorigenesis and influence cancer progression. Numerous databases are utilized to conduct searches for articles, such as NCBI, MEDLINE, and Scopus. The keywords used throughout the academic archives are "circadian rhythm", "cancer", and "circadian clock". Maintaining a healthy circadian cycle involves prioritizing healthy sleep habits and minimizing disruptions, such as consistent sleep schedules, reduced artificial light exposure, and meal timing adjustments. Dysregulation of the circadian clock gene and cell cycle can cause tumor growth, leading to the need to regulate the circadian cycle for better treatment outcomes. The circadian clock components significantly impact cellular responses to DNA damage, influencing cancer development. Understanding the circadian rhythm's role in tumor diseases and their therapeutic targets is essential for treating and preventing cancer. Disruptions to the circadian rhythm can promote abnormal cell development and tumor metastasis, potentially due to immune system imbalances and hormonal fluctuations.

Keywords: cancer; circadian rhythm; melatonin; suprachiasmatic nucleus.

Figure 1

The connection between melatonin secretion and circadian rhythm. The suprachiasmatic nuclei (SCN), which are located immediately above the optic chiasm in the anterior-ventral area of the hypothalamus, are believed to include the pacemaker of this clock. This circadian clock reset comes about through the retinohypothalamic tract (RHT), which sends light information directly from the retina to a subset of SCN neurons. A pineal hormone known as melatonin is most abundant in the blood at night and least prevalent during the day. Its secretion is governed by a rhythm-generating process in the SCN, which is regulated by light. Melatonin is not only regulated by the circadian oscillator but also provides the oscillator with a feedback signal for darkness. Bilateral structure of the SCN and its “core” and “shell” subregions with vasoactive intestinal peptide (VIP) and gastrin-releasing peptide (GRP) in the light-responsive core and arginine vasopressin (AVP)-expressing cells in the shell; optic chiasm (OC); the 3rd cerebral ventricle (V3).

Figure 2

p53 controls the metabolism in cells that are proliferating. p53 suppresses phosphoglycerate mutase (PGM), hexokinase, TP53-induced glycolysis, and apoptosis regulator (TIGAR), and it represses glucose transporters 1 and 4 (GLUT1 and GLUT4). These actions prevent glycolysis from occurring and counteract the Warburg effect, which is observed in many malignancies. The synthesis of glutaminase 2 (GLS2) and cytochrome c oxidase 2 (SCO2) is induced by p53, which increases oxidative phosphorylation. Using IKK/NF-κB signaling, p53 can also control the glycolytic pathway. The Warburg effect is also affected by miRNA dysregulation. miR-143 regulates glycolysis. The miR-200 family controls phosphoglucose isomerase, which is also connected to carcinogenesis. GLUT1 mRNA is a direct target of miR-378a, which limits carcinogenesis and suppresses glucose metabolism in PCa cells. miR-378 influences the TCA cycle in breast cancer. (FAc), fatty acid; TCA, tricarboxylic acid cycle; (−), inhibition; (+), stimulation.

Figure 3

The development of cancer characteristics has been attributed to changes in the circadian rhythm. Circadian rhythms and the cell cycle: DNA replication and the cell cycle present a particular circadian pattern. Circadian rhythms are seen in the expression of DNA replication and cell cycle regulators. Furthermore, different cell cycle genes are modulated by circadian cycle genes. This way, three concepts are tightly regulated: DNA damage response, repair, and circadian rhythms. Cryptochrome 1/2 (CRY1/2). Also, numerous metabolic functions, including the tricarboxylic cycle (TCA) and glucose, are changed by an adequate circadian rhythm. In addition, due to the modification of the malignant medium, vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1-alpha (HIF1α) is highly expressed.

Figure 4

Disrupted circadian rhythm and molecular pathways in the development of cancer. By blocking NF-κB and HIF1α from translocating to the nucleus, melatonin inhibits pathways related to survival and inflammation via binding to the MT1 and MT2 receptors. To activate the transcription of clock-controlled genes (CCGs), RORα, REV-ERBα, CRY (1-2), PER (1-3), and BMAL1 and CLOCK heterodimerize and bind to the E-box. BMAL and CLOCK heterodimer inhibition by CRY and PER creates the main negative feedback loop. BMAL1’s transcription is inhibited by REV-ERBα, while RORα is activated in the secondary feedback loop.

Figure 5

Chronobiological methods for preventing and treating cancer and its associated disorders. Different diseases can be the result of disruptions to the circadian rhythm. Thus, a deeper understanding of the relationship between the two may prevent cancer. In this way, three categories of chronotherapeutic therapies are important. (1) Clocking the drugs: maximizing drug timing to enhance efficacy and minimize negative side effects; circadian rhythms significantly impact the pharmacokinetics and pharmacodynamics of medication responses. The effectiveness and bioavailability of the medications are influenced by rhythmic changes, which might range from drug absorption to target receptor expression. (2) Administering the clock: using small-molecule drugs that specifically target a circadian clock. (3) Training the clock: appropriate strategies to improve or sustain a healthy circadian periodicity in feeding–fasting, sleep–wake, or light-dark cycles.