Home Medizin Die Studie gibt Aufschluss über die Rolle des Enzyms beim fortgeschrittenen Fortschreiten des Prostatakrebses

Die Studie gibt Aufschluss über die Rolle des Enzyms beim fortgeschrittenen Fortschreiten des Prostatakrebses

von NFI Redaktion

Prostate cancer is the second most common cancer in men, after skin cancer, with over 288,000 new cases diagnosed every year, according to the American Cancer Society. While mortality rates for this disease have dropped by more than half since the 1990s, there is still room for improvement, especially in the treatment or prevention of advanced, metastatic diseases, which are much more likely to be fatal.

A new paper published in Science Advances explains how an enzyme called SMYD3 could be involved in the progression of prostate cancer to a more dangerous and aggressive stage, making it a potential target for drugs to prevent metastasis.

Redefined Role of an Enzyme

Researchers have been trying to explain the role of SMYD3 in cancer since it was observed that it occurs unusually frequently in cancerous tumors compared to healthy tissue, according to Erin Green, Associate Professor of Biological Sciences at the University of Maryland, Baltimore County (UMBC) and lead author of the article.

„This protein is of great interest,“ says Green. „However,“ she adds, „the literature has been conflicting.“

Several previous studies suggested that SMYD3 acts in the cell nucleus and regulates which genes the cell expresses by directly modifying DNA. However, investigations led by Nicolas Reynoird, a scientist at the Institute for Advanced Biosciences in Grenoble, France and co-author of the new study, suggested a different mechanism.

In a key 2014 study published by Reynoird as a postdoctoral fellow at Stanford, he and his colleagues found that SMYD3 acts outside the cell nucleus and activates a kind of protein called MAP kinase. MAP kinases are overactive in cancer cells and can promote tumor growth.

The new Science Advances article, led by Sabeen Ikram, a postdoctoral fellow at Stanford University, built on Reynoird’s previous work. Ikram’s experiments conclusively and in detail demonstrated how SMYD3 could trigger metastasizing prostate cancer via the MAP kinase signaling pathway. The new work for the first time establishes a connection between an excess of SMYD3 and excessive activation of the MAP kinase signal in prostate cancer, renewing interest in SMYD3 as a therapeutic target.

Exciting Insights from All Angles

The research team demonstrated in cells in a petri dish and in mice that the addition of methyl groups (three hydrogen atoms bound to a carbon atom) to MAP kinase is likely to play a role in SMYD3’s role in metastasis. In experiments with inactivated SMYD3, the likelihood of metastasis was significantly lower.

Compounds that can inactivate SMYD3, called inhibitors, are already available, according to Green. Ikram conducted experiments with one of these inhibitors and found that it effectively killed cancer cells in a petri dish. The team is looking to conduct the same experiments in mice to further confirm the compound’s effect. They also want to investigate whether targeting SMYD3 could help combat cancers that develop resistance to other treatments.

Ikram’s experiments also found that SMYD3 led to increased activity of a protein called Vimentin, which is well studied as a marker of cancer progression. Interestingly, the effect of SMYD3 was specific to Vimentin, even though it belongs to a large group of similar proteins.

Finally, the new study found, for the first time, that SMYD3 creates a positive feedback loop in the cell, where high levels of SMYD3 contribute to maintain the excess.

A New Direction and New Hope for Patients

Green sees many possibilities for future work.

„So far, we have only examined this mechanism in prostate cancer, but I think it is likely to occur in other types of cancer cells as well. That is another thing we want to further investigate: How common is this?“

Erin Green, Associate Professor of Biological Sciences, University of Maryland, Baltimore County (UMBC)

Green is also excited about the potential use of SMYD3 as a therapeutic target for prostate cancer and other cancers. Since there are already SMYD3 inhibitors, the new findings could encourage companies to invest in discovering new applications for them.

„There are drugs that have not been fully explored because people have decided that there is no good target,“ says Green. „So there could be a lot more done there.“

Source:

University of Maryland, Baltimore County

Journal reference:

Ikram, S., et al. (2023). The SMYD3-MAP3K2 signaling axis promotes tumor aggressiveness and metastasis in prostate cancer. Science Advances. doi.org/10.1126/sciadv.adi5921.

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