Tumor Growth Promoted by Circadian Rhythm Disruptions

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Circadian dysregulation of the cell cycle
Circadian dysregulation of the cell cycle increases tumor growth and time-dependent anti-cancer activity of PD-0332991. [Amita Sehgal]

Researchers at the University of Pennsylvania report that disrupting normal circadian rhythms promotes tumor growth and suppresses the effects of a tumor-fighting drug. The team, which published its study (“G1/S cell cycle regulators mediate effects of circadian dysregulation on tumor growth and provide targets for timed anticancer treatment”) in PLOS, says the results provide mechanistic support for “chronotherapy,” the delivery of cancer drugs timed to the endogenous circadian rhythm.

“Circadian disruption has multiple pathological consequences, but the underlying mechanisms are largely unknown. To address such mechanisms, we subjected transformed cultured cells to chronic circadian desynchrony (CCD), mimicking a chronic jet-lag scheme, and assayed a range of cellular functions. The results indicated a specific circadian clock–dependent increase in cell proliferation. Transcriptome analysis revealed up-regulation of G1/S phase transition genes (myelocytomatosis oncogene cellular homolog [Myc], cyclin D1/3, chromatin licensing and DNA replication factor 1 [Cdt1]), concomitant with increased phosphorylation of the retinoblastoma (RB) protein by cyclin-dependent kinase (CDK) 4/6 and increased G1-S progression,” the investigators wrote.

“Phospho-RB (Ser807/811) was found to oscillate in a circadian fashion and exhibit phase-shifted rhythms in circadian desynchronized cells. Consistent with circadian regulation, a CDK4/6 inhibitor approved for cancer treatment reduced growth of cultured cells and mouse tumors in a time-of-day–specific manner. Our study identifies a mechanism that underlies effects of circadian disruption on tumor growth and underscores the use of treatment timed to endogenous circadian rhythms.”

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 tumor growth, 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 cell cycle. Circadian rhythm disruption increased cell proliferation, an effect that could be traced to increased expression of cyclin D1, a cell-cycle control protein. 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 circadian rhythms 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,” said Amita Sehgal, PhD, John Herr Musser professor of neurosciences, Perelman School of Medicine, University of Pennsylvania. “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, and to better treatment strategies, including timing delivery of cancer therapy for maximum benefit.”

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