Cancer cells change the biological clock in order to survive

Cancer cells change the biological clock in order to survive

January 2, 2018 Source: Biological Exploration of: Flora

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Often, cells regulate their protein expression based on the natural “day and night cycle” to establish their own biological clock and control their metabolism. However, studies have shown that the circadian rhythm in tumor cells is different from normal cells.

Considering that protein expression is closely related to cell circadian rhythms, the J. Alan Diehl team from the Hollings Cancer Center at the Medical University of South Carolina presented a new hypothesis that misfolded proteins may alter the circadian rhythm of cancer cells.

　 ▋ 1. What is “unfolded protein reaction”?

The endoplasmic reticulum is an important place for protein folding. Once the burden is too heavy, there will be cases where the protein is not folded or misfolded. For this abnormality, cells activate the unfolded protein response (UPR) to slow down the synthesis of new proteins, increase the ability of the endoplasmic reticulum to fold proteins, and accelerate the degradation of misfolded or unfolded proteins. This stress signaling pathway helps cells maintain homeostasis and prevent apoptosis.

Cancer cells are very good at using the UPR reaction to improve their ability to expand. But how do cancer cells use the UPR mechanism to influence circadian rhythms? This is not clear.

â–‹ 2, UPR will change the biological clock of cancer cells

To validate the speculation, the research team used chemicals to activate the UPR mechanism of cancer cells. It was found that once activated, UPR changes the expression level of a key protein, Bmal1.

Bmal1 is a transcription factor that alternates up- or down-regulation with day and night to regulate the orderly expression of genes downstream of the circadian rhythm. Specifically, in the dark, the amount of Bmal1 expression reaches its peak. However, once the UPR mechanism is activated, Bmal1 will remain low, resulting in changes in circadian rhythm-related gene expression.

The researchers found that the UPR response acts like an "intermediate contact" that performs duties between the natural circadian cycle and the cell clock. Once UPR is activated, the circadian rhythm protein Bmal1 levels will continue to decrease, changing the cell circadian clock.

Hollings Cancer Center researchers Dr. Yiwen Bu and Dr. J. Alan Diehl explore how cancer overrides the circadian clock to survive. Credit: Hollings Cancer Center

â–‹ 3. What does this change mean for cancer development?

The team found that the higher the Bmal1 protein level in patients with breast, stomach and lung cancer, the longer the survival time.

Moreover, for MYC-driven cancers, the UPR mechanism causes a decrease in Bmal1 protein and promotes tumor growth. Such cancer cells lose normal circadian rhythms. Conversely, once the Bmal1 protein is overexpressed, it replaces the UPR mechanism, allowing normal expression of circadian rhythm-related genes, thereby suppressing tumor growth.

For the first time, this study confirmed that cancer cells disrupt circadian rhythms by inhibiting Bmal1 protein synthesis. Once the Bmal1 protein is inhibited, the survival of cancer cells will be prolonged. "This result reminds us that doctors need to consider treatment time. For example, taking drugs at a certain time is more beneficial to improve the targeting effect and reduce the impact on normal cells." Yiwen Bu said.

Original title: Nature's sub-publication: In order to survive cancer cells, "quietly" change the biological clock

Reference: Cancer overrides the circadian clock to survive

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