Circadian rhythms and cancer
Cancer occurs due to a malfunction of the internal clock
A team of scientists from Berlin described the connection between the cell life cycle and the mechanism of the internal clock at the molecular genetic level. It has been shown how disruption of the internal clock contributes to the formation of cancerous tumors.
The internal clock was developed in living organisms on Earth as a result of evolutionary adaptation to the periodic change of day and night. At the molecular genetic level, daily or circadian changes in metabolism, hormone levels, immune functions, drug metabolism, as well as changes in rest and activity cycles are determined by changes in the work of genes (their expression) and changes in the amount of proteins produced by them.
In mammals, two loops are known to control the circadian clock, each of which consists of a sequence of molecules and genes affecting each other: one controls the expression of genes from the families Per (from the word "period") and Cry (from the word "cryptochrome"), the second regulates the work of the Bmal1 gene.
It was previously shown that the operation of these loops is influenced by a component of the cell signaling system – genes of the Ras family, which, firstly, are associated with the cell life cycle, that is, with the transition of the cell from a state of growth to a state of division or specialization, and secondly, are considered oncogenes, that is, genes in which mutations they lead to unlimited cell division, to the appearance of a cancerous tumor.
In other words, the occurrence of cancerous tumors is associated with the influence of the Ras oncogene on the circadian clock and the subsequent change in the cell life cycle. The molecular mechanism of this process was to be found out by scientists.
The researchers found that the Ink4a and Arf genes, which are important elements of both systems, play a central role in the multi-way schemes of interaction between the cell cycle and the circadian clock, and violations of their work are associated with the transformation of cells into cancer. The "shutdown" of these genes against the background of excessive RAS protein content led to a shortened circadian period (through the influence on the Per and Cry genes) and to increased cell division. The Bmal1 gene was also involved in this scheme.
These experimental data obtained on mouse embryonic fibroblasts (non-specialized cells), into which the luminous enzyme luciferase was "hooked" to fix periodic diurnal fluctuations, were also confirmed by a mathematical model that was built on published data on genes and proteins involved in the circadian clock and controlling the cell life cycle.
The link between the cell cycle and the circadian clock described by scientists, namely the Ink4a and Arf genes, which at the same time are tumor suppressor genes that prevent cell transformation and thus prevent the occurrence of cancer, confirmed the hypothesis of scientists that the normal operation of the circadian clock prevents the occurrence of cancerous tumors.
The therapeutic effect on the circadian clock, as well as the coordination of drug treatment with cellular rhythms, can increase the effectiveness of cancer treatment, which will be a new step in chronotherapy.
The study is published in the journal PlOS Biology (El-Athman et al., The Ink4a/Arf locus operates as a regulator of the circadian clock modulating RAS activity).
Circadian rhythms are extremely important for the normal functioning of the body. For the discovery of molecular mechanisms that control circadian rhythms, Americans Michael Young, Jeffrey Hall and Michael Rosbash received the Nobel Prize in 2017.
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