Aspirin Prevents Diseases by Controlling Nucleolar Stress

Nucleoli participate in the formation of signal recognition particles and play a role in the cell's response to stress. Nucleoli comprise proteins, DNA, and RNA and form around specific chromosomal regions called nucleolar organizing regions. Malfunction of nucleoli can be the cause of several human conditions called nucleolopathies, and the nucleolus is being investigated as a target for cancer chemotherapy.

The tumor suppressor gene p53 is well known as an effector of nucleolar stress, but p53 independent mechanisms are largely unknown. Like p53, the NF-kappaB transcription factor plays a critical role in maintaining cellular homeostasis under stress. Many stresses that stimulate NF-kappaB also disrupt nucleoli. However, the link between nucleolar function and activation of the NF-κB pathway is as yet unknown.

Towards a better understanding of nucleolar stress, investigators at the University of Edinburgh (United Kingdom) studied this phenomenon in cell cultures and tumor biopsy specimens removed from colon cancer patients.

They reported in the June 5, 2018, online edition of the journal Nucleic Acids Research that artificial disruption of the PolI (DNA polymerase iota) complex stimulated NF-kappaB signaling. Unlike p53 nucleolar stress response, this effect did not appear to be linked to inhibition of rDNA (ribosomal DNA) transcription. Specific stress stimuli of NF-kappaB induced degradation of a critical component of the PolI complex, TIF-IA. This degradation preceded activation of NF-kappaB and was associated with increased nucleolar size.

Blocking TIF-IA degradation with aspirin blocked stress effects on nucleolar size and NF-kappaB signaling. This was demonstrated by showing a strong correlation between degradation of TIF-IA and activation of NF-kappaB in colorectal tumor biopsy cultures exposed to aspirin.

Senior author Dr. Lesley Stark, senior lecturer on the cancer research center at the University of Edinburgh, said, "We are really excited by these findings as they suggest a mechanism by which aspirin may act to prevent multiple diseases. A better understanding of how aspirin blocks TIF-IA and nucleolar activity provides great promise for the development of new treatments and targeted therapy."

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