Cancer Cells Hijack Circadian Rhythm for Survival

Cancer cells could take advantage of the unfolded protein response (UPR) to adapt the circadian rhythm in a way that accelerates tumor growth, according to a study published by Nature Cell Biology.

Tumor cells have to produce larger quantities of nucleic acids and proteins in order for cancer to proliferate and metastasize. For both normal cells and cancer cells with increased protein production, a number of the proteins do not fold correctly, according to the study authors.

When proteins are folded incorrectly, the cell activates the UPR, which reduces the rate of protein production while misfolded proteins are refolded. However, the build-up of misfolded proteins can be toxic and result in cell death, according to the study.

To mitigate toxicity and the build-up of misfolded proteins, cancer cells have developed a way to harness the UPR to reduce protein synthesis and survive, according to the study.

"What a tumor cell is doing is taking a pathway that's already in the cell and using it to its advantage," said senior researcher J. Alan Diehl, PhD.

Previously, it was unclear how cancer cells harnessed the UPR to alter circadian rhythm.

The authors of the current study discovered that the UPR and circadian rhythm are linked so they can govern the clockwork of the cell. They also found that cancer cells use the UPR to change circadian rhythm to help them survive toxic conditions, according to the study.

The researchers said they previously knew that UPR was altered in cancer cells and that cells have a circadian rhythm that regulates metabolism by producing protein levels that rise and fall with the cycles of light and dark. They also noted that other studies have found that circadian rhythm is altered in cancer cells.

The authors of the current study hypothesized that misfolded proteins may alter circadian rhythm in cancer cells because protein production is tied to the cycle.

First, the authors chemically activated the UPR in osteosarcoma cells and discovered there were changes in the levels of the Bmal1 protein. This crucial protein rises and falls during the day and night and regulated the expression of circadian rhythm genes, according to the authors.

Bmal1 levels peaked during dark house when the cells were exposed to cycles of light and dark. When the UPR was chemically activated, the authors discovered that the protein activity remained low during both cycles, causing a phase shift in circadian gene expression, according to the study. When a main part of the UPR was missing in the cells, the phase shift did not occur.

These results suggest that the UPR functions are a middleman that goes between light and dark cycles, according to the study. As the UPR was activated, levels of Bmal1 continued to decrease, the authors found.

When the light-dark cycles were reversed in animal models, Bmal1 levels stopped increasing and falling, which indicated that there was a disruption in circadian rhythm, according to the study.

The authors noted that patients with breast, gastric, or lung cancers had increased survival if they had higher levels of Bmal1 expression.

In myc-related cancers, the UPR resulted in the loss of Bmal1, which resulted in cancer growth. Myc-driven cancers were found to lose circadian rhythm, while normal cells were unaffected, according to the study. However, the authors also found that high levels of Bmal1 took over the UPR and allowed protein synthesis to continue and become toxic to cancer cells.

This was the first study that showed cancer can suppress the circadian rhythm through controlling protein synthesis, according to the investigators.

"Every single normal cell in our body has circadian oscillation," said first author Yiwen Bu, PhD. "We showed that resetting the circadian rhythms in cancer cells slows down their proliferation."

It is currently unclear whether circadian rhythm shifts affect UPR and contribute to cancer growth in humans, but if this is proven in clinical trials, it could help increase the efficacy of current therapies, according to the study.

"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," Dr Bu said.