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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. For tumors 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 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 tumor cells. 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. Researchers formulated a new idea based on what was known about protein synthesis in the cell. 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.
Scientists had observed that circadian rhythm is altered in tumor cells. Since protein production is tied to circadian rhythm. 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.
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.
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 tumor cells . In this way, Bmal1 directly encourages protein synthesis.
Human cancer suppresses circadian rhythm by controlling protein synthesis 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. Every single normal cell in human body has circadian oscillation, resetting the circadian rhythms in cancer cells slows down their proliferation.
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