【Nature】Heavyweight | Scientists from New York University Discover New Tumor Suppressors, Becoming Potential Treatments

This article is converted Medicine original, reproduced please indicate the source Author: Yun Introduction: The recent study found that during embryonic development, a kind of enzyme protein on the cell cycle control for normal cell growth is essential, it The dysfunction can lead to fatal cell overgrowth.

Recently, researchers have discovered a long-awaited enzyme that can prevent cancer by breaking down driver proteins.

Like the developing fetus, restricting cell division is the key to preventing abnormal and aggressive growth in cancer.
New research has found that cells have evolved to use AMBRA1 to defend against it.

The research was published in "Nature" magazine, entitled "CRL4AMBRA1 is a master regulator of D-type cyclins".

Cells have the ability to divide continuously, and this process will continue to repeat until a fertilized egg cell becomes a body with trillions of cells.

For each division, the cell must follow certain steps, most of which are promoted by proteins called cyclins.

The work, led by researchers at New York University’s Grossman School of Medicine, revealed that an enzyme called AMBRA1 marks key cyclins, which can be destroyed by cellular machinery that breaks down proteins.

This study found that during embryonic development, this enzyme's control of cyclin is essential for the normal growth of cells, and its dysfunction can lead to fatal cell overgrowth.

In addition, this study further shows that existing drug classes may be able to reverse this shortcoming in the future.

"Our research clarifies the basic characteristics of human cells, provides insights into cancer biology, and opens up new research avenues for potential treatments," said New York University Langone Department of Health, Department of Biochemistry and Molecular Pharmacology.
Said Dr.
Michele Pagano.

The current research on the new tumor suppressor targets three D-type cyclins.
If cells are to divide, they must be linked to cyclin-dependent kinases (CDKs), especially CDK4 and CDK6.

The study found that AMBRA1 acts as a ligase, attaching molecular tags to all three D-type cyclins, marking them for destruction.

The previously proposed mechanism by which D-type cyclin is cleared by cells cannot be replicated by the scientific community.

Therefore, Pagano said that prior to this new study, the central regulator of D-type cyclin had been elusive for a quarter of a century.

This new work also reveals the role of AMBRA1 in development.

Mice lacking the AMBRA1 gene encoding the AMBRA1 enzyme develop uncontrolled lethal tissue growth that deforms the developing brain and spinal cord.

Researchers also found for the first time that using CDK4/6 inhibitors to treat pregnant mice carrying embryos without the AMBRA1 gene can reduce these neuronal abnormalities.

In terms of cancer, the authors analyzed the patient database and concluded that patients with lower-than-normal AMBRA1 expression are less likely to survive in diffuse large B-cell lymphoma (the most common non-Hodgkin lymphoma in the United States).

Reasons for the decreased expression of AMBRA1 may include random changes that delete genes or make the encoded instructions more difficult to read.

To confirm the role of AMBRA1 as a tumor suppressor, the researchers collaborated with research author Dr.
Luca Busino of the University of Pennsylvania to monitor the growth of cancer cells in a mouse model of diffuse large B-cell lymphoma.

For example, when human B-cell lymphoma cells were transplanted into mice, tumors without the AMBRA1 gene grew three times faster than tumors with the gene.

While the study led by New York University focused on diffuse large B-cell lymphoma, two other studies led by Stanford University and the Danish Cancer Society Research Center were published in the same issue of Nature.
The study found that the absence or disability of AMBRA1 is The key factor of lung cancer.

In addition, D-type cyclin is known to assemble with CDK4 and CDK6 into enzymes that can promote the growth of normal and abnormal cells.

In recent years, drugs that inhibit CDK4 and CDK6 have been approved by the FDA as cancer therapies, but some patients have a weak response to the drugs.

In order to understand this issue in depth, the current research team found that lymphomas lacking AMBRA1 are less sensitive to CDK4/6 inhibitors.

When the AMBRA1 gene is deleted, the level of D-type cyclin becomes high enough to form a complex with another CDK (CDK2), which cannot be inactivated by CDK4/6 inhibitors due to its structure.

"This makes AMBRA1 a potential marker for selecting patients most suitable for CDK4/6 inhibitor therapy," said first author Dr.
Daniele Simoneschi, a senior research coordinator in the Department of Biochemistry and Molecular Pharmacology at New York University Langone Health.

As a next step, he said, the research team plans to study the combined effects of CDK4/6 inhibitors and CDK2 inhibitors on tumors with low levels of AMBRA1 and tumors with D-type cyclin mutations that are not sensitive to AMBRA1.

Reference materials: [1] https://medicalxpress.
com/news/2021-03-safer-mri-contrast-agent-high-resolution.
html [2] 021-00687-z Note: This article aims to introduce the progress of medical research and cannot be used as a reference for treatment options.

If you need health guidance, please go to a regular hospital for treatment.