Cancer Overrides The Circadian Clock to Survive
Source: Medical University of South Carolina
Summary: Researchers found that tumor cells use the unfolded protein response to alter circadian rhythm, which contributes to more tumor growth. 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. In normal and cancer cells which increase their protein synthesis, a small amount of protein do not fold properly. This results in the activation of unfolded protein response (UPR), which further slows down the making of new proteins while the misfolded proteins are refolded. Eventually, the accumulation 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. Researchers from the Medical University of South Carolina found that tumor cells use the unfolded protein response to alter circadian rhythm, which contributes to more tumor growth. A key part of the circadian clock opposes this process. The research findings were published in the journal Nature Cell Biology.
The research team in their first set of experiments used chemicals to activate the UPR in osteosarcoma cells. They found that, when activated, the UPR changes the levels of Bmal1 protein, 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. They 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.
Senior researcher J. Alan 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 cancer and less toxicity in the normal cells.”
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