It was thought for many years that a family of enzymes, residing in the outer surface of cell membranes, only role was isolated to cell adhesion functions. However, as researchers continued to study the signaling pathways associated with tumorigenesis they kept noticing one of these surface enzymes in particular was heavily involved in the proliferation of different cancer cells. That specific enzyme, the metallopeptidase ADAM17, was discovered to cleave tumor necrosis factor-α and have a direct role in carcinogenesis. Still, the pathway that leads to the enzyme’s activation has eluded scientists for a number of years, until now.
Danish researchers from the University of Copenhagen have discovered the mechanism that they believe controls the enzyme and aids the growth of cancerous tumors—which could prove to be of great value for the development of new chemotherapeutic interventions.
“ADAM17 is very important to the growth of cancer tumors. It functions as a molecular pair of scissors, separating molecules from the cell's surface which then increases cell growth. The problem being that in cancer cells this growth is over-activated and so the cancer tumors grow rapidly and uncontrollably,” explained lead author Sarah Dombernowsky, Ph.D., postdoctoral researcher in the Department of Biomedicine & BRICK at Copenhagen Biocenter.
The findings from this study were published recently in Nature Communications through an article entitled “The sorting protein PACS-2 promotes ErbB signalling by regulating recycling of the metalloproteinase ADAM17.”
Understanding the mechanisms that lead to the activation of ADAM17 has been of importance to scientists for a number of years, since initial drugs developed to inhibit the enzyme’s activity generated compounds that caused severe side effects in cancer patients. In this study, the Danish researchers were able to show that a sorting protein, typically involved in transporting molecules from the endoplasmic reticulum to the mitochondria, was crucial to the translocation of ADAM17.
“We have discovered that the protein PACS-2 plays a big part in the transportation of ADAM17 in cells. ADAM17 moves in and out of the cell, but it has to remain on the surface to be able to cut off molecules and thus further growth. We have showed that without the PACS-2, ADAM17 returns less regularly to the surface; it's broken down instead,” stated Dr. Dombernowsky.
Using mice that were deficient in PACS-2, the investigators were able to control ADAM17 cell-surface availability by diverting the enzyme away from degradation pathways, hence regulating its overall cleavage activity.
“There have been attempts at developing a pill to inhibit ADAM17, only the patients became ill due to side effects, because other, similar enzymes were also affected. But if you inhibit PACS-2, you can, in principle, obstruct only ADAM17, which would enable us to inhibit the growth of the cancer tumor,” Dr. Dombernowsky said.
Dr. Dombernowsky was excited by her and her collaborator’s initial findings and she plans to expand her analysis of the ADAM17 pathway through the use of various animal models.
“We're currently experimenting on mice to see if the cancer growth slows down, and it is our distinct expectation that it will. In the long-term, we would like to develop something that through PACS-2 allows us to fine-tune ADAM17, which could then eventually become part of a more targeted cancer treatment,” Dr. Dombernowsky concluded.