Circadian rhythm disruption tips the cell-cycle balance toward tumor growth

Circadian rhythm disruption tips the cell-cycle balance toward tumor growth
Circadian dysregulation of the cell cycle increases tumor growth and time-dependent anti-cancer activity of PD-0332991. Credit: Amita Sehgal

Disrupting normal circadian rhythms promotes tumor growth and suppresses the effects of a tumor-fighting drug, according to a new study publishing April 30 in the open-access journal PLOS Biology by Yool Lee, Amita Sehgal, and colleagues at the University of Pennsylvania. The results provide mechanistic support for "chronotherapy," the delivery of cancer drugs timed to the endogenous circadian rhythm.

Circadian rhythms regulate many aspects of physiology from the organismic to the subcellular levels. Disruption of circadian rhythms, whether through jet travel, shift work, or sleep disturbances, is a known risk factor for several types of cancer. In animal models, hormonally induced circadian disruption promotes , but the underlying mechanism or mechanisms have not been clear.

To uncover potential mechanisms, the authors used the hormone dexamethasone to chronically advance daily rhythms in cultured cells. They found that treatment altered expression of multiple genes, especially those involved in regulating the . Circadian rhythm disruption increased , an effect that could be traced to increased expression of a cell-cycle control protein called cyclin D1. Cyclin D1, in turn, activated cyclin D-dependent kinase 4/6 (CDK4/6), a protein that switched the cell from growing larger to synthesizing new DNA, a step that ultimately leads to cell division.

Because tumor growth is linked so tightly to cell division, many cancer treatments seek to arrest progression through the cell cycle. The authors found that the tumor-fighting ability of one such drug, called PD-0332991, which inhibits CDK4/6 activity, varies with time-of-day such that treatment in the morning is more effective than treatment at night. Efficacy of PD-0332991 was reduced in both cells and mice when their were disrupted.

"We suggest that chronic disruption of the normal circadian rhythm tips the balance between tumor-suppressive and tumor-progressive gene expression to favor tumor growth," Sehgal said. "Better understanding 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, and to better treatment strategies, including timing delivery of cancer therapy for maximum benefit."


Explore further

Researchers discover how eating feeds into the body clock

More information: Lee Y, Lahens NF, Zhang S, Bedont J, Field JM, Sehgal A (2019) G1/S cell cycle regulators mediate effects of circadian dysregulation on tumor growth and provide targets for timed anticancer treatment. PLoS Biol 17(4): e3000228. doi.org/10.1371/journal.pbio.3000228
Journal information: PLoS Biology

Citation: Circadian rhythm disruption tips the cell-cycle balance toward tumor growth (2019, April 30) retrieved 18 July 2019 from https://medicalxpress.com/news/2019-04-circadian-rhythm-disruption-cell-cycle-tumor.html
This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.
2582 shares

Feedback to editors

User comments

May 01, 2019
Most of the references are mouse models, else night shift workers so serious disruptions at that.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more