Scientists at the Florida campus of The Scripps Research Institute (TSRI) say they have reinforced the idea that the ribosome assembly process is a potentially fertile new target for anticancer drugs by detailing the essential function of a key component in that process.

“This study confirms that ribosome assembly is a good therapeutic target in cancer,” said Katrin Karbstein, Ph.D., a TSRI associate professor who led a study (“Hrr25/CK1δ-directed release of Ltv1 from pre-40S ribosomes is necessary for ribosome assembly and cell growth”), which is published in The Journal of Cell Biology. “Whether or not we have pinpointed the best molecule remains to be shown, but this is a vindication of our basic research. There should be effort devoted to exploring this pathway.”

Understanding ribosome assembly, which involves about 200 essential proteins known as “assembly factors” in addition to the four RNA molecules and 78 ribosomal proteins that are part of the mature ribosome, has become a fruitful area of research in recent years because of the importance of ribosome assembly for cell growth.

The new study highlights the molecules casein kinase 1δ (CK1δ) and CK1ε, which are essential for human ribosome assembly. The expression of CK1δ is elevated in several tumor types, as well as Alzheimer's and Parkinson's disease, and CK1δ inhibitors have shown promise in some preclinical animal studies.

In the new study, Dr. Karbstein and her group, working closely with three labs across the state of Florida, including the laboratory of William Roush at Scripps Florida, used Hrr25, the yeast equivalent of casein kinase 1δ (CK1δ) and CK1ε, as a research model.

In biochemical experiments, the team showed that Hrr25 is necessary for ribosome assembly and that the molecule normally adds a phosphate group to an assembly factor called Ltv1, allowing it to separate from other subunits and mature. If Hrr25 is inactivated or a mutation blocks the release of Ltv1, the assembly process is doomed.

“Ltv1 knockdown in human breast cancer cells impaired apoptosis induced by CK1δ/ε inhibitors, establishing that the antiproliferative activity of these inhibitors is due, at least in part, to disruption of ribosome assembly,” wrote the investigators.

“Inhibiting Hrr25 and the subsequent release of Ltv1 blocks the formation of other subunits that are required for maturation and the subsequent production of proteins,” said Homa Ghalei, Ph.D., the first author of the study and a member of the Karbstein lab.

In additional experiments on human breast cancer cells, the researchers showed that CK1δ/CK1ε inhibitors no longer induce apoptosis and prevent cancer cells from growing when Ltv1 is removed.

“[Our] findings validate the ribosome assembly pathway as a novel target for the development of anticancer therapeutics,” noted Dr. Karbstein.