Our circadian rhythm—the biological clock that dictates when we become sleepy or alert—is essential to healthy functioning. A disrupted circadian rhythm is known to wreak havoc on the human body, causing abnormal behavioral and hormonal rhythms, cognitive discrepancies, weight gain, diabetes, increased cell death, and in some cases, cancer. However, the molecular, biochemical, or cellular mechanisms that underlie the effects of circadian rhythm disruption have until now remained a mystery.
To better understand these underlying mechanisms, scientists exposed transformed cultured cells to chronic circadian desynchrony (CCD), putting the cells under the equivalent conditions of chronic jet-lag. The investigators found that there was a specific circadian clock-dependent increase in cell proliferation. They also discovered that a CDK4/6 inhibitor drug used for cancer treatment diminished cell growth of the cultured cells and mouse tumors when used chronotherapeutically, a treatment method that takes into account the body's natural rhythms and cycles.
"We suggest that chronic disruption of the normal circadian rhythm tips the balance between tumor-suppressive and tumor-progressive to favor tumor growth," commented Amita Sehgal, PhD, Professor of Neuroscience at the University of Pennsylvania and lead author of the study, published in PLoS Biology. "Better understanding of the molecular effects of jet lag, shift work, and other sources of chronic disruption may lead to strategies to minimize the increased cancer risk associated with these behaviors as well as to better treatment strategies, including timing delivery of cancer therapy for maximum benefit."
The investigators solved another crucial piece of the mystery: enduring CCD stimulates phosphorylation of the retinoblastoma protein, supporting G1/S phase cell cycle progression. The CDK4/6 inhibitor drug targets the enzyme that phosphorylates the retinoblastoma protein and hinders cancer cell growth. The drug has to be administered chronotherapeutically to achieve maximum effectiveness, and this study showed that the time dependence of this drug is abolished by chronic jet-lag conditions.
The study authors concluded, "These data suggest a circadian regulation of G1/S cell cycle progression and provide an important molecular rationale for time-of-day-specific treatment of cancer patients, also known as chronotherapy."
For More Information
Lee Y, Lahens NF, Zhang S, et al (2019). G1/S cell cycle regulators mediate effects of circadian dysregulation on tumor growth and provide targets for timed anticancer treatment. PLoS Biol. [Epub ahead of print] DOI:10.1371/journal.pbio.3000228
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