One of the trickiest things about anti-cancer drug design is targeting. Today, most drugs on the market target critical cell cycle or cell surface proteins, with new research identifying new targets every day.
In a new study out of the University of Toyama in Japan, a team conducted a screen and identified a possible protein target for cancer therapeutics. This target, called PMSD14, was tied to something called the proteasome, which has been on researchers’ radar for potential cancer therapeutics for a while now.
The proteasome is the primary protein disposal tool in most cells. An old or defective protein is tagged with something called ubiquitin, which targets that protein to the proteasome. The proteasome then shreds it into small pieces. The protein that the team identified is called PSMD14, which is responsible for un-tagging ubiquitinated proteins. It has also been linked to cancer in other studies.
The study first identified PSMD14 as a promoter of melanoma growth. The team then attempted to figure out the mechanism in which it worked. They analyzed genes that correlated one way or another with PSMD14’s loss. The team then examined how PSMD14 loss in melanoma cells affected growth and metastatic characteristics.
They began by knocking out the PSMD14 gene in a melanoma cell line. A previous study pointed to this knockout affecting cell cycle inhibitor proteins p21 and RB. The cell cycle is how cells grow and divide, so its inhibition effectively kills a cell. Indeed, PSMD14 knockout upregulated p21 expression and activated RB. Therefore, inhibiting PSMD14 with a drug could activate these two cell cycle inhibitors and impair melanoma growth.
The proteasome presents an interesting but complex target for anti-cancer therapeutics. This study shines a light on not the proteasome but on one of its assisting proteins. PSMD14 knockout in melanoma results in the activation and upregulation of CDK inhibitors RB and p21, which impairs the growth of melanoma cells in vitro. Targeting PSMD14 would allow scientists to selectively target the proteasome without inducing catastrophic dysfunction, although far more research needs to be done to ensure it would work.
The study concludes, “Although we identified PSMD14 as a molecular target for melanoma, there is currently no available drug targeting PSMD14. As the disturbance of proteasome function by PSMD14 knockdown may affect melanoma growth, proteasome inhibitors, including bortezomib, may be attractive drugs for melanoma.”
Sources: Nature Scientific Reports, Myeloma UK