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Cancerous cells by definition are constantly growing and multiplying and therefore have devised ways to sustain that growth. If one wishes to create a brand new therapeutic against cancer, it’s necessary to identify molecular mechanisms that cancer cells use to grow, then attempt to shut down that mechanism with a small molecule or other drugs. Here we focus on a crucial signaling process in cells driven by a small protein modifier called ubiquitin that is currently the subject of much interest to those hunting for new cancer treatments.
In 2004, the Nobel Prize in Chemistry was awarded to Hershko, Ciechanover, and Rose for “the discovery of ubiquitin-mediated protein degradation”. Only the previous year, the FDA approved bortezomib in humans, the first drug ever devised to directly target the outcome of ubiquitin signaling. Since then, bortezomib, marketed as Velcade, has been used to treat over half a million patients worldwide for multiple myeloma, according to its official website.
How long do proteins last in our bodies? You may be surprised to know that most given proteins in mammals have a half-life of only about a day in actively dividing cells. Proteins become worn out and/or grow unnecessary as time goes on, just like any tools we use in our world. Therefore, it’s crucial for cells to have a way to get rid of and recycle unwanted proteins. This concept, which is called protein turnover, allows our cells to keep their proteins fresh and up-to-date. Typically, protein turnover is performed by a signaling pathway driven by the ubiquitin-proteasome system.
For a cell to degrade an unwanted protein, it must first identify and place a signal on that protein. This signal is ubiquitin, which itself is a mini protein that is present in all eukaryotic organisms, with humans being no exception. But attaching ubiquitin is no simple task since marking a protein for destruction is a process that can’t be taken lightly and requires delicate regulation. There are three steps required for a protein to be ubiquitinated – E1 (activation), E2 (conjugation), and E3 (ligation). Once the ubiquitin is attached to a lysine residue of the target protein, it can then be recognized by the proteasome, a large cellular structure that performs the dirty work of taking apart the target protein. You can almost think of it as a big shredder, taking apart the protein into its component amino acids so that they can be re-used by the cell for making new proteins. Only by ubiquitination can a protein be recognized and destroyed by the proteasome.
Now cancer cells, in their constant state of growth depend on the ubiquitin-proteasome system quite a bit. For every step in the cell cycle, new proteins are required and old proteins need to be recycled. Non-dividing cells tend to keep their proteins around for longer, degrading them less often. You may be smelling an opportunity for a cancer therapy here and you are not alone. In 2003, bortezomib became the first in a class of drugs known as proteasome inhibitors. Since then two more proteasome inhibitors have entered the market; carfilzomib and ixazomib, with more currently in clinical trials.
The mechanism of proteasome inhibitors is rather simple; these drugs block the proteasome from performing its function of degrading proteins. Therefore, cells experience a buildup of proteins, including proteins like p53 that are a signal for the cell to kill itself in a process called apoptosis. The beauty in this type of drug is that it is especially effective against actively dividing cells, and less so against non-dividing cells. Since cancer cells fall squarely in the former category, the ubiquitin-proteasome system is a ripe target for new anticancer treatments. Only last year, a team of researchers discovered an inhibitor of the ubiquitin-activating enzyme (E1) that had antitumor activity in mice.
There exists a myriad of other aspects of the ubiquitin system that we do not yet understand completely. For instance, a topic of intense research is the study of enzymes that can remove ubiquitin from ubiquitinated proteins, aptly named deubiquitinases. Ubiquitin signaling is crucial for protein degradation but is also intimately involved in other important cellular functions such as DNA damage repair and immunity – both of which have some importance when thinking about cancers. A better understanding of how our cells employ ubiquitin signaling in these different situations will surely lead to new tools and therapeutics in the fight against cancer.
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