An enzyme involved in cell stress responses could become a new pharmacological target in the treatment of liver cancer, a disease that currently has few available treatment options. The research team has discovered that the protein p38 gamma, one of the four types of p38 kinase, is essential for the initiation of cell division in liver cells. This indicates that "p38 gamma could be a useful therapeutic target for liver cancer," says the author, adding, "we are now developing inhibitors of this protein to test in this cancer." The study has been published in Nature.

"The four members of the p38 kinase family are so similar that at first they appear to have overlapping or redundant functions," says the senior author. "But detailed analysis of their three-dimensional structures revealed that one of the four, p38 gmmma, also shares close similarities with another family of proteins called CDKs. These proteins are well-known regulators of cell division and the cell cycle and play a well-established role in the development of cancer."

In laboratory studies exploring this similarity to CDKs, the team found that an inhibitor of CDK2 also reduced the activity of p38 gamma. The researchers also found that p38gamma and CDK2 both act on a tumor suppressor protein that plays a central role in the regulation of the cell cycle.

To test whether p38 gamma is implicated in cell division, study first author examined the outcome of chemically inducing liver cancer in mice that lack the enzyme. The results were truly promising: "in mice lacking p38 gamma or treated with inhibitors to block its activity, the development of hepatocellular carcinoma was slowed," says the author.

These results, says the senior author, "could be extrapolated to human patients." Indeed, they show that the amount of p38gamma increases with liver fibrosis, a process that precedes cancer and is much higher in liver cancer patients. These results suggest that in the future it may be possible to treat this type of cancer with drugs that specifically target p38gamma. The advantage of targeting p38gamma is that this enzyme appears to control the initiation of the cell cycle in response to stress, and therefore inhibiting this process would not affect tissues that are constantly proliferating, like the intestinal lining or hair follicles.

https://www.cnic.es/en/noticias/nature-protein-p38gamma-identified-new-therapeutic-target-liver-cancer

https://www.nature.com/articles/s41586-019-1112-8