Cancer overrides circadian clock to survive, says study

For tumours to grow and spread, cancer cells must make larger than normal amounts of nucleic acids and protein, so they can replicate themselves.

Cancer overrides circadian clock to survive, says study
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Washington: Cancer cells suppress the body's circadian clock by controlling protein synthesis, which contributes to more tumour growth, according to a study.

The finding could help clinicians boost the effectiveness of current cancer treatments, researchers said.

For tumours to grow and spread, cancer cells 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 per cent 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.

Now, researchers at the Medical University of South Carolina (MUSC) in the US have found that 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, they said.

This pattern of adaptation is often seen in tumour cells, according to J Alan Diehl, senior researcher on the paper published in the journal Nature Cell Biology.

"What a tumour cell is doing is taking a pathway that is already in the cell and using it to its advantage," said Diehl.

Researchers 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 circadian clock in ways that allow them to survive conditions that are toxic to normal cells.

A circadian rhythm is a roughly 24 hour cycle in the physiological processes of living beings.

In their first set of experiments, the 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.

However, 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.

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 tumours to grow.

Myc-driven tumours 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 tumour cells. In this way, Bmal1 directly encourages protein synthesis.

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