New findings about cancer cell growth may hold promise for future cancer treatments

Date:
August 5, 2021
Source:
Karolinska Institutet
Summary:
For a cell to grow and divide, it needs to produce new
proteins. This also applies to cancer cells. Researchers have now
investigated the protein eIF4A3 and its role in the growth of cancer
cells. The study shows that by blocking or reducing the production
of this protein, other processes arise that cause the growth and
cell division of cancer cells to cease and eventually die.



FULL STORY ==========================================================================
For a cell to grow and divide, it needs to produce new proteins. This
also applies to cancer cells. In a new study published today in Science Advances, researchers at Karolinska Institutet in Sweden have investigated
the protein eIF4A3 and its role in the growth of cancer cells. The study
shows that by blocking or reducing the production of this protein, other processes arise that cause the growth and cell division of cancer cells
to cease and eventually die.


==========================================================================
The body's normal cell division is carefully controlled, where
genes in the cell regulate when it is time to start and stop cell
division. Sometimes this balance is disturbed and the cell continues
to divide uninhibitedly. After some time, a small collection of cells
develops -- cancer may be about to form.

"When a cell grows, new proteins are produced, among other things, through
the translation of the cell's DNA information into mRNA, which forms the
basis for the creation of proteins. The cell also needs to manufacture
rRNA for the cell's small factories, the ribosomes, which are responsible
for producing proteins," says Associate Professor Mikael Lindstro"m,
co-author and part of Professor Jiri Bartek's research group at the
Department of Medical Biochemistry and Biophysics who conducted the study.

In the study, the research group investigated cultured cancer cells and
cancer tissue where the eIF4A3 protein's expression was high compared
to normal tissue. By adding synthetically produced small molecules that
can later be further developed into finished drugs, the production of
eIF4A3 can be checked.

The researchers then discovered two distinct changes in the cancer cells.

"Firstly, we saw that the blocking of eIF4A3 activated the protein p53,
a protein that has an important role to play in fighting cancer cells,"
says Dimitris Kanellis, a postdoctoral fellow at the Department of
Medical Biochemistry and Biophysics, and the first author of the study.

However, one challenge with many types of tumours is that the positive functions of the p53 protein are counteracted by another protein, MDM2.

"Interestingly, we noted that the blocking eIF4A3 also meant that the
MDM2 protein changed. This change helps to maintain and strengthen p53
and can be beneficial when we want to inhibit the growth of cancer cells," continues Dimitris Kanellis.

The main conclusions of the study indicate that depletion or inhibition
of eIF4A3 activates p53, alters the manufacturing process of proteins by disrupting ribosome biogenesis, and thereby inhibits the growth of cancer cells. Knowledge of the importance of the eIF4A3 protein opens up new opportunities for better and more effective treatment of cancer patients.

"The discovery is very relevant as this type of targeted treatment
may represent a new possible approach in chemotherapy, for example in
colon cancer where cancer cells often have a high level of ribosomes
and rapid growth.

Another example is a sarcoma, cancer of the body's support tissues, where
we know that sometimes there is an overproduction of MDM2. This increases
the chances of more effective treatment," says Associate Professor Mikael Lindstro"m and Professor Jiri Bartek, corresponding authors in the study.

These findings provide an important foundation for further
studies. However, since the study has mainly been carried out in cultured cancer cells and clinical tumour material, it remains to be seen how
the blocking of eIF4A3 will affect the growth of cancer in vivo.

"There may also be synergies between the chemical compounds that block
eIF4A3 and drugs that are already used to treat cancer that we will now research further," concludes Mikael Lindstro"m.

The research was funded by the Swedish Research Council, the Cancer
Foundation, the Swedish Childhood Cancer Foundation, ERC, and Karolinska Institutet.

========================================================================== Story Source: Materials provided by Karolinska_Institutet. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Dimitris C. Kanellis, Jaime A. Espinoza, Asimina Zisi, Elpidoforos
Sakkas, Jirina Bartkova, Anna-Maria Katsori, Johan Bostro"m,
Lars Dyrskjo/t, Helle Broholm, Mikael Altun, Simon J. Elsa"sser,
Mikael S.

Lindstro"m, Jiri Bartek. The exon-junction complex helicase
eIF4A3 controls cell fate via coordinated regulation of ribosome
biogenesis and translational output. Science Advances, 2021; 7
(32): eabf7561 DOI: 10.1126/sciadv.abf7561 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210805141149.htm

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