Circadian clocks are cell-autonomous timing systems that have approximately 24-hour periodic rhythms that are conserved in nearly all life. They integrate diverse environmental and metabolic stimuli to regulate biological activities, such as immune functions and cell proliferation. One of our speakers this semester, Fred Turk talked about the circadian clock and the importance of clock genes in many different scenarios. Disturbances in these rhythms caused by sleep deprivation, eating at night, or chronic jet lag are closely associated with the development of sleep and mood disorders, obesity, diabetes, and cancer. Specifically genetic and environmental perturbations of circadian rhythms largely alter the expression and activity of several tumor suppressors and oncogenes in both host and tumor tissues to favor cancer incidence and progression. Circadian disruptions can also reprogram host metabolism and immune systems, fostering an immunosuppressive tumor microenvironment in multiple cancer types. Because of this Circadian rhythms are an emerging target for cancer prevention and treatment. Cancer therapy by enhancing circadian rhythms, modulating the activity of circadian clock molecules, and optimizing the icing of anticancer drugs according to the host or tumor circadian rhythms.
Circadian rhythm is characterized by a cell autonomous autoregulatory feedback loop. Positive and negative clock regulators form transcriptional translational feedback loops that drive the rhythmic expression of genes involved in metabolic, biosynthetic, signal transduction, and cell cycle pathways. Multiple levels of regulation contribute to the molecular clockwork thereby coordinating programs by clock genes. There are approximately 20,000 oscillators or a specific group of genes that are expressed in a rhythmic pattern or periodic cycles, in individual neurons and astrocytes in the hypothalamic suprachiasmatic nucleus (SCN) region of the brain. The SCN is considered a central circadian pacemaker or the master clock because its main role is to communicate retinal light information to peripheral clock systems. This connects internal body rhythms with external day and night cycles. It coordinates these rhythms via rhythmic release of neurotransmitters and neuropeptides. The phases in non-SCN regions are signaled by systemic hormone secretion. Rhythmic disturbances by physiological and environmental factors impact pathogenesis in diseases like cancer.
The disruption of circadian rhythmicity is a common thing in modern society since the invention of artificial light sources. 80% of the world’s promulgation is now exposed to light during the night, and approximately 18-20% of workers in the USA and Europe have night or rotating shift work, making them vulnerable to multiple rhythm disorders, including cancer. Studies suggest that night shift work or chronic jet lag increases the risk of the incidence and envelope, met of the most common cancer types. In a different study, mouse models were exposed to forced circadian desynchrony regimens and this reinforced the causal relationship between circadian disturbances and cancer pathogenesis. Damage to the SCN, which is the experimental version of chronic jet lag (CJL), has been shown to cause alteration in circadian physiology and significantly accelerated the growth rates of transplanted tumors. CJL has also been shown to accelerate tumor cell cycle progression and growth rates in carcinogen-induced tumors in mice.
Circadian disruptions dysregulated many important processes in the body like the cell cycle, DNA repair, apoptosis, senescence, autophagy, and other oncogenic and immune pathways. This dysregulation causes uncontrolled proliferation, escape from apoptosis, metastatic spread, immune evasion, enhanced angiogenesis, and anticancer drug resistance, all of these are characteristics of cancer. There is a direct involvement of clock genes in cancer predisposition and development. Also, the overexpression of circadian activators suppress proliferative and malignant phenotypes in tumor cells. There is a proposed anticancer mechanism that centers around a circadian gene that is supposedly involved in the mediation of glycolysis and the induction of cell cycle arrest and apoptosis. In humans, 32 cancer types were revealed that several clock genes are downregulated in multiple cancers.
Circadian rhythm based therapies or chronotherapeutic approaches to disease treatment are categorized into three different types. The first being training the clock, which entails interventions to enhance or maintain a robust circadian rhythm in feeding-fasting, sleep-wake, or light-dark cycles. The second is drugging the clock, which uses small-molecule agents to directly target a circadian clock. And thirdly, clocking the drugs, which optimizes the timing of drugs to improve efficacy and reduce adverse side effects. These can be used in a combinatorial fashion. An example of a chronotherapeutic tool used to mitigate cancer progression, is morning bright light (MBL) exposure. MBL has been widely implemented to cure sleep problems, neuropsychiatric diseases, and metabolic disorders. Studies have shown that melatonin depletion by light exposure late at night stimulates the growth of multiple human cancer xenografts and increases anticancer drug resistance.
Extensive chronobiological research has expanded the understanding of the functional roles and mechanism of the circadian clockwork in human health and disease, including cancer. Circadian disruption negatively impact tumor molecular clocks and host circadian systems to increase cancer risk and progression. Chronophysiological or chronotherapeutic interventions is thought to benefit overall circadian health and cancer therapy.
Lee, Y. (2021). Roles of circadian clocks in cancer pathogenesis and treatment. Experimental & Molecular Medicine, 53(10), 1529–1538. https://doi.org/10.1038/s12276-021-00681-0
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