Disruption of the circadian rhythm tilts the balance of the cell cycle towards tumor growth

Disruption of normal circadian rhythms promotes tumor growth and suppresses the effects of an anti-tumor drug, according to a new study published April 30 in the journal open-access PLOS Biology by Yool Lee, Amita Sehgal and colleagues at the University of Pennsylvania. The findings provide mechanical support for "chronotherapy", the administration of anticancer drugs to the endogenous circadian rhythm.

Circadian rhythms regulate many aspects of physiology, from organismic levels to subcellular levels. Disruption of circadian rhythms, whether by air travel, shift work or sleep disorders, is a known risk factor for many types of cancer. In animal models, circadian disruption of hormonal origin promotes tumor growth, but the underlying mechanism (s) have not been clearly defined.

To discover the potential mechanisms, the authors used the hormone dexamethasone to progress chronically the daily rhythms in cells in culture. They discovered that the treatment impaired the expression of several genes, particularly those involved in cell cycle regulation. Disruption of the circadian rhythm increases cell proliferation, an effect that could be attributed to increased expression of the cell cycle control protein termed cyclin D1. Cyclin D1 in turn activated the cyclin D-dependent 4/6 kinase (CDK4 / 6), a protein that made the cell grow larger and larger at the synthesis of a new DNA, a step which ultimately leads to cell division.

Since tumor growth is closely related to cell division, many cancer treatments seek to arrest progression in the cell cycle. The authors found that the tumor control power of a drug of this type, called PD-0332991, which inhibits the activity of CDK4 / 6, varies with the time of day, from so the treatment in the morning is more effective than the night treatment. The efficacy of PD-0332991 was reduced in both cells and mice when their circadian rhythms were disrupted.

"We suggest that a chronic disruption of the normal circadian rhythm tilts the balance between the expression of tumor suppressor genes and progressive tumors to promote tumor growth," Sehgal said. "A better understanding of the molecular effects of jet lag, shift work, and other sources of chronic disruption may help develop strategies to minimize the increased risk of cancer associated with these behaviors, as well as better treatment strategies, including cancer treatment planning for maximum benefit. "