Cancer overrides the circadian clock to survive

December 28, 2017, Medical University of South Carolina
Hollings Cancer Center researchers Dr. Yiwen Bu and Dr. J. Alan Diehl explore how cancer overrides the circadian clock to survive. Credit: Hollings Cancer Center

Tumor cells use the unfolded protein response to alter circadian rhythm, which contributes to more tumor growth, Hollings Cancer Center researchers at the Medical University of South Carolina (MUSC) find. A key part of the circadian clock opposes this process, according to a paper published online Dec. 11 in Nature Cell Biology.

For tumors to grow and spread, cancer must make larger than normal amounts of nucleic acids and protein, so they can replicate themselves. Yet in both normal and cancer cells that increase their synthesis of protein, a small percent of those proteins do not fold properly. When that happens, the cell activates its unfolded protein response (UPR), which slows down the making of new proteins while the misfolded proteins are refolded. Eventually, the buildup of misfolded proteins becomes toxic and leads to cell death. However, cancer cells have learned to use the UPR to slow protein synthesis when needed, in order to handle the backlog of misfolded proteins. This helps them survive in conditions that would kill normal cells.

This pattern of adaptation is often seen in cells, according to J. Alan Diehl, Ph.D., the SmartState Endowed Chair in Lipidomics, Pathobiology and Therapy at the MUSC Hollings Cancer Center and senior researcher on the project. "What a tumor cell is doing is taking a pathway that's already in the cell and using it to its advantage," said Diehl.

Yet it was not clear exactly how cancer cells were able to use UPR activity to influence circadian . Diehl's group found that the UPR and circadian rhythm are linked together to lead the clockwork of the cell and also that cancer cells use the UPR to manipulate the in ways that allow them to survive conditions that are toxic to normal cells.

To start, Diehl and his fellow researchers formulated a new idea based on what was known about protein synthesis in the cell. First, as they knew, the UPR is altered in tumors, and second, cells establish a circadian rhythm to regulate metabolism by producing levels of certain proteins that rise and fall in coordination with natural cycles of light and dark. Third, other scientists had observed that circadian rhythm is altered in tumor cells. Since protein production is tied to circadian rhythm, Diehl's group asked if misfolded proteins might change circadian rhythm in cancer cells.

In their first set of experiments, Diehl's research team used chemicals to activate the UPR in osteosarcoma cells. They found that, when activated, the UPR changes levels of an important protein called Bmal1, which is a transcription factor that rises and falls with cycles of light and dark. As it does, it regulates the expression of major circadian rhythm genes. When cells were exposed to cycles of light and dark, Bmal1 levels peaked during dark hours. But when the UPR was chemically activated, Bmal1 stayed low during both light and dark phases, which caused a phase shift in the expression of circadian genes. When one of the main parts of the UPR machinery was absent in cells, the phase shift did not happen.

Next, the group found that the UPR functions much like a "middleman" between light-dark cycles and the ability of cells to establish a circadian rhythm from those cycles. Levels of the circadian protein Bmal1 continued to decrease, as the UPR was increasingly activated. In rodents that had their light-dark cycles suddenly reversed, Bmal1 stopped rising and falling - a clear sign that their circadian rhythms were disrupted. Shifts in light exposure activated the UPR in those rodents' cells.

But what does that mean for the development of cancer?The team found that patients with breast, gastric or lung cancers survived longer when they had higher levels of Bmal1 protein. In myc-driven cancers, the UPR was causing the loss of Bmal1 protein, which caused the tumors to grow. Myc-driven tumors lost circadian rhythm, whereas normal cells maintained it. Conversely, high levels of Bmal1 overtook the UPR, thereby allowing protein synthesis to continue, which was toxic to . In this way, Bmal1 directly encourages synthesis.

This is the first study showing that human cancer suppresses circadian rhythm by controlling through Bmal1. Cancer cells survived longer by using the UPR to suppress Bmal1 and short-circuit their circadian rhythms. These results are important for human biology, according to Yiwen Bu, Ph.D., a postdoctoral scholar in Diehl's laboratory and first author on the paper. "Every single normal cell in our body has circadian oscillation," said Bu. "We showed that resetting the in slows down their proliferation."

Still, do changes in light-dark cycles contribute to the development of cancer in humans? It is not yet clear in patients if circadian shifts contribute to changes in the UPR and if that, in turn, contributes to the development of cancer. But these results could help clinicians boost the effectiveness of current cancer treatments, Diehl said.

"Physicians are beginning to think about timing delivery of therapies in such a way that, say, if we deliver a drug at a certain time of day, we'll get better on-target effects on the and less toxicity in the ," he said.

Explore further: Time matters: Does our biological clock keep cancer at bay?

More information: Yiwen Bu et al, A PERK–miR-211 axis suppresses circadian regulators and protein synthesis to promote cancer cell survival, Nature Cell Biology (2017). DOI: 10.1038/s41556-017-0006-y

Related Stories

Time matters: Does our biological clock keep cancer at bay?

December 7, 2017
Our body has an internal biological or "circadian" clock, which cycles daily and is synchronized with solar time. New research done in mice suggests that it can help suppress cancer. The study, publishing 7 December in the ...

Potassium is critical to circadian rhythms in human red blood cells

December 12, 2017
An innovative new study from the University of Surrey and Cambridge's MRC Laboratory of Molecular Biology, published in the prestigious journal Nature Communications, has uncovered the secrets of the circadian rhythms in ...

Link between biological-clock disturbance and brain dysfunction found

October 30, 2017
Researchers at Okayama University report in the Journal of Neuroscience that a certain protein known to play a major role in circadian rhythmicity—humans' intrinsic 24-hour biological cycle—is also key to proper brain ...

New study reveals a link between circadian clock disruption and tumor growth

July 29, 2016
A handful of large studies of cancer risk factors have found that working the night shift, as nearly 15 percent of Americans do, boosts the chances of developing cancer. MIT biologists have now found a link that may explain ...

Cancers don't sleep: The Myc oncogene can disrupt circadian rhythm

April 9, 2013
The Myc oncogene can disrupt the 24-hour internal rhythm in cancer cells. Postdoctoral fellow Brian Altman, PhD, and graduate student Annie Hsieh, MD, both from the in the lab of Chi Van Dang, MD, PhD, director of the Abramson ...

Cancer doesn't sleep: Myc oncogene disrupts clock and metabolism in cancer cells

September 17, 2015
Myc is a cancer-causing gene responsible for disrupting the normal 24-hour internal rhythm and metabolic pathways in cancer cells, found a team led by researchers from the Perelman School of Medicine at the University of ...

Recommended for you

Discovery of inner ear function may improve diagnosis of hearing impairment

October 15, 2018
Results from a research study published in Nature Communications show how the inner ear processes speech, something that has until now been unknown. The authors of the report include researchers from Linköping University, ...

Team's study reveals hidden lives of medical biomarkers

October 12, 2018
What do medical biomarkers do on evenings and weekends, when they might be considered off the clock?

Widespread errors in 'proofreading' cause inherited blindness

October 12, 2018
Mistakes in "proofreading" the genetic code of retinal cells is the cause of a form of inherited blindness, retinitis pigmentosa (RP) caused by mutations in splicing factors.

Researchers create a functional salivary gland organoid

October 11, 2018
A research group led by scientists from Showa University and the RIKEN Center for Biosystems Dynamics Research in Japan have, for the first time, succeeded in growing three-dimensional salivary gland tissue that, when implanted ...

Lassa fever vaccine shows promise and reveals new test for immunity

October 11, 2018
Lassa fever belongs to the same class of hemorrhagic fevers as Ebola. Like Ebola, it has been a major health threat in Western Africa, infecting 100,000-300,000 people and killing 5,000 per year. A new vaccine against both ...

Genetically engineered 3-D human muscle transplant in a murine model

October 10, 2018
A growing need for tissues and organs in surgical reconstruction is addressed by the promising field of tissue engineering. For instance, muscle atrophy results from severe traumatic events including deep burns and cancer, ...

0 comments

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

Click here to reset your password.
Sign in to get notified via email when new comments are made.