The process of recycling involves taking waste and turning it into something new. I think we can all agree that humans could be better at recycling, but fortunately, we don’t have that same concern for the cells that comprise us. In our cells, we have millions of proteins that are constantly being made and degraded… a kind of ebb and flow of having the proteins that the cell needs to function and survive and degrading the proteins that are broken or not needed at that time. In regards to degradation, the cell has a built in recycling center called the proteasome. When a protein is no longer needed, the proteasome chops it up for parts and those parts go on to be used to make new proteins – recycling!

 

Cancer cells are especially dependent on their proteasomes because they are constantly dividing to make more and more cancer cells. They want to quickly and efficiently degrade any anti-cancer proteins, broken proteins… any proteins that could impede their rapid division.

With this knowledge, proteasome inhibitors started being used to kill cancer cells. When the proteasome is inhibited, there is an accumulation of not needed proteins that need to be degraded. This accumulation really stresses out the cell, and if the stress persists long enough, the cell will kill itself - great for cancer treatment. Proteasome inhibitor therapy works well to kill certain blood cancer cells, but unfortunately, most tumor cells (such as breast cancer) utilize a proteasome bounce-back response to overcome proteasome inhibition. When proteasomes are inhibited, cells activate a transcription factor, NRF1, which tells the cell to make more proteasomes. The new proteasomes are able to recycle the accumulating proteins and relieve the stress, so the cell survives. Part of the activation of the transcription factor NRF1 involves a protease DDI2, which acts as a pair of molecular scissors to cut NRF1 into its active form. A protease is a much more promising drug target than a transcription factor, so the goal of my research is to determine if a combinational approach of proteasome inhibition and DDI2 inhibition to block the bounce-back response can better kill breast cancer cells, which proteasome inhibition alone doesn’t do. The American Cancer Society predicts that 1 in 3 individuals will develop some type of cancer during their lifetime, so our hope is that this combinational therapy will expand the repertoire of cancer types in which proteasome inhibitors can successfully kill cancer cells and improve patient outcomes.