Researchers at the NYU Grossman School of Medicine have identified an enzyme that prevents cancer by enabling the breakdown of proteins that drive cell growth.
The discovery came when investigating cell proliferation, the process of cell division from a single cell to the trillions of cells that comprise the body. The process of cell division is promoted by a class of regulatory proteins known as cyclins, which help to control the cell cycle. Their studies identified an enzyme named AMBRA1 which labels certain cyclins for destruction through cellular mechanisms that break down proteins.
During embryonic development, AMBRA1 is essential, as without it, cell proliferation malfunctions leading to massive cell overgrowth which is fatal. During fetal development, constraints on cell proliferation is essential otherwise cell division can occur at high rates similar to the aggressive growth seen in cancers. The researchers suggest that AMBRA1 evolved as a control mechanism to keep cell division in check.
In order for cells to divide, three D-type cyclins must link up with enzymes called cyclin-dependent kinases (CDKs), specifically CDK4 and CDK6. When the cyclin binds, it activates the CDK, and the CDK activates the target protein to regulate the cell cycle, after which the cyclin is destroyed.
The researchers found that AMBRA1, as a ligase, attaches molecular tags to all three D-type cyclins and labels them for destruction. While for over a quarter of a century it has been known that D-type cyclins were eliminated by cells, the central regulator of D-type cyclins has not been discovered until now.
The researchers demonstrated that AMBRA1 plays a key role in development. Mice engineered to lack the AMBRA1 gene that codes for the enzyme developed uncontrolled tissue growth that destroyed the developing brain and spinal cord and proved lethal. When the mice were treated with a CDK4/6 inhibitor, pregnant mice carrying embryos that lacked the AMBRA1 gene had fewer abnormalities.
The role that AMBRA1 may play in cancer was also investigated. Patients with lower levels of AMBRA1 were found to be less likely to survive diffuse large B-cell lymphoma. When human B-cell lymphoma cells were transplanted into mice, the tumors grew three times as quickly without the AMBRA1 gene. Two separate studies conducted at Stanford University found a defective or missing AMBRA1 gene also played a key role in lung cancer.
CDK4 and CDK6 inhibitors are currently approved for use in cancer treatment, but they are more effective in some patients than others. The researchers found that lymphomas that lack AMBRA1 are less sensitive to CDK4/CDK6 inhibitors. Levels of D-type cyclins then become sufficiently high to form complexes with CDK2, which the CDK4/CDK6 inhibitors cannot inactivate. AMBRA1 could therefore be used as a marker for selecting patients that would most likely benefit from CDK4/CDK6 inhibitor cancer therapy.
“Our study clarifies basic features of human cells, provides insights into cancer biology, and opens new research avenues into potential treatments,” said corresponding study author Michele Pagano, MD, chair of the Department of Biochemistry and Molecular Pharmacology at NYU Langone Health.
You can read more about the study in the paper – CRL4AMBRA1 is a master regulator of D-type cyclins – was published on April 14, 2021 in Nature. DOI: 10.1038/s41586-021-03445-y