The influence of metabolism on cancer growth and development is a large focus of current research projects. Researchers have looked into the influence of amino acids and other metabolites on their ability to aid tumor growth. It has been previously discovered that deprivation of serine, an amino acid that is used to build proteins, can inhibit the growth of tumors in mouse models. A recent study published from Johns Hopkins School of Medicine has found that mutations in spliceosomes inhibit chemical processes that are necessary to produce serine.
Spliceosomes are complexes of RNA and protein that are involved in processing newly synthesized RNA to a mature form that is used to make proteins. In various cancer types like breast carcinomas, leukemias, and melanomas, it is known that mutations in the SF3B1 gene are a cause of spliceosome mutations. These mutations essentially create nonsense transcripts that are unable to make a functional protein and are subsequently targeted for destruction. In order to better study this mutation, the researchers created a model in which they introduced SF3B1 mutations into noncancerous breast cells.
Image Source: shunyufan
The results from this cell model showed that the SF3B1 mutation inhibits the serine biosynthesis pathway which is responsible for the production of serine. The main enzyme of this pathway that was negatively affected was PHGDH, which is critical in the production of serine. When investigating how the SF3B1 mutation changes tumor cells, the researchers found reduced PHGDH protein levels in the cells. Further investigation found that these mutations led to mis-spliced PHGDH RNA and then the subsequent inhibition of the serine biosynthesis pathway. Splicing is the process where unnecessary portions of the RNA transcript are removed to create a mature RNA strand that can make a protein. The combination of these factors made these cells sensitive to serine and more dependent on taking up serine from external sources. To confirm this, the researchers found that overexpression of PHGDH was able to compensate for the errors in splicing from SF3B1 mutations.
Lastly, the researchers investigated the influence of serine deprivation on the growth of leukemia tumors. They found that these tumors grew slowly from the lack of serine compared to cells that were supplied with serine. This data further supports previous findings that decreasing serine can inhibit the growth of tumors. This is beneficial as normal cells do not contain these mutations and would not be affected by serine deprivation since they have the ability to make their own.
This research further contributes to the growing dialogue on the importance and influence of metabolism in terms of targeting cancer growth. The SF3B1 mutation can open the door for a new treatment option because the mutations are localized to tumors, which means that the serine depletion would not affect healthy cells as they are capable of making their own serine. Therefore, it is possible a low-serine diet could limit and restrict tumor growth while minimally harming other cells in the process.
Featured Image Source: PDPics
