Recently, researchers from the Hollings Cancer Center at the University of Southern Carolina Medical School (MUSC) discovered that tumor cells use unfolded protein response (UPR) to change the biological clock, which further leads to tumor growth as a key part of the biological clock precisely inhibits the tumor growth process. Related study results being published in the Nature Cell Biology.
Cancer cells must generate abnormally large amounts of nucleic acids and proteins, which constantly replicate themselves so that the tumor cells will grow and proliferate. However, in normal cells and cancer cells that increase protein synthesis, a small portion of the protein does not fold properly. Under this condition, cells activate the unfolded protein response (UPR), which will slow down the production of new proteins, and the misfolded proteins are refolded. Eventually, the accumulation of misfolded proteins creates toxicity and leads to cell death. However, cancer cells have learned to use UPR to slow protein synthesis and thus control the accumulation of misfolded proteins. This may help cancer cells survive in an environment that kills normal cells.
Dr. J. Alan Diehl of Hollings Cancer Center said that, ‘Usually we find this adaptive pattern in tumor cells. What the tumor cells do is to use the special pathways which already exist in the cell to serve themselves.’
However, it is not yet clear how cancer cells use UPR activities to influence circadian rhythms. Diehl's team found that the UPR and the biological clock are closely related, which controls the day-to-night conclusion of the cells. The cancer cells use the UPR to manipulate the biological clock and enable them to survive in environments where normal cells cannot survive.
Diehl and his colleagues proposed a new idea based on known information about protein synthesis in cells. At first, they knew UPR was changed in the tumor, and then cells establish a circadian rhythm that regulates metabolism by controlling the levels of specific proteins. The level of these proteins rises and falls with the natural rhythms of the night and day. Furthermore, other scientists observed that the biological clock in tumor cells was changed. Because protein production is related to the biological clock, Diehl's team wanted to find out if the misfolded protein changed the circadian rhythm of cells.
In their first experiments, Diehl's team used chemicals to activate UPR in osteosarcoma cells. They found that when UPR is activated, UPR can change the level of an important protein called Bmal1 (also named ARNTL), which is a transcription factor that changes constantly with day and night levels. It regulates the expression of the major biological clock genes. When cells participate in the diurnal cycle, Bmal1 levels will get the peak at night. However, the level of Bmal1 will stay low during the night and day while UPR is chemically activated, which can cause changes in circadian gene expression. If one of the major parts of the UPR mechanism is missing, the above-mentioned changes will not happen.
Further, the research team found that the UPR function is just like a ‘middle man’ as it can help establish the circadian rhythm of cells, and the Bmal1 protein level will continue to decline with the unfolded protein response is highly activated. In mice whose circadian rhythm is reversed, Bmal1 will stop rising and falling. This is a clear indication that the biological clock has been disrupted. Changes in light can activate UPR in rodent cells.
But what does this mean for the formation of cancer? The team found that breast cancer, gastric cancer, and lung cancer patients with higher levels of Bmal1 protein survive longer. In MYC-driven cancers, UPR can cause the loss of Bmal1 protein, which can lead to tumor growth. The MYC-driven tumor loses its circadian rhythm while normal cells maintain circadian rhythms. In contrast, high levels of Bmal1 can overwhelm the UPR, allowing protein synthesis to continue, which is detrimental to tumor cells, Bmal1 can directly promote protein synthesis with this method.
This is the first study to show that human cancer can inhibit circadian rhythm by controlling protein synthesis by Bmal1, inhibiting Bmal1 and short-circuiting its circadian rhythm by using UPR, and cancer cells will survive longer. Dr. Yiwen Bu of Diehl Lab said, ‘These results are very important for human biology. Every normal cell in our body has a biological clock. We have found that resetting the biological clock in cancer cells can effectively slow their proliferation.’
However, whether the changes in the circadian cycle can lead to human cancer? Currently, it is not clear whether changes in circadian rhythms will lead to changes in UPR and whether this will, in turn, lead to cancer. However, these results can help clinicians improve the effectiveness of current cancer treatments. For example, whether it is possible to treat cancers on a regular basis if taking medications at specific times of the day, may be possible to get a better therapeutic effect on cancer and less toxicity on normal cells.
Reference:
Bu Y, Yoshida A, Chitnis N, et al. A PERK-miR-211 axis suppresses circadian regulators and protein synthesis to promote cancer cell survival. Nature Cell Biology, 2017, 20(1).