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Scientists ID Natural Control Mechanism for ADAM17, a Key Metalloproteinase Involved in the Progression of Many Cancers; New Approach Might Eliminate Side-Effects Seen with Drug Inhibitors of ADAM17

Researchers from the University of Copenhagen in Denmark have discovered what regulates an enzyme that is central to the growth of cancer tumors. This could be of great value to future cancer treatment. Danish researchers from the University of Copenhagen have discovered what controls the enzyme that aids the growth of cancer tumors. These findings could be of great value to cancer treatments and they were published online on June 25, 2015 in Nature Communications. The enzyme is called ADAM17 (image), a metalloproteinase, and it aids growth in cells. The article is titled: The Sorting Protein PACS-2 Promotes ErbB Signalling by Regulating Recycling of the Metalloproteinase ADAM17.” "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 tumor grows rapidly and uncontrollably," Postdoc Dr. Sarah Dombernowsky explains. She is a member of Associate Professor Marie Kveiborg's research group at the Department of Biomedicine & BRICK, at Copenhagen Biocenter. Researchers from all over the world have long been interested in finding ways to restrict ADAM17 and thus inhibit the growth of cancerous tumors. Among other things, they have tried to impede the process with different drugs. However, these drugs also obstructed other important scissors, which led to patients suffering severe side effects. This is why it is of such great importance that Dr. Dombernowsky and her colleagues have now identified a mechanism that controls 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," Dr. Dombernowsky elaborates.

Thus, ADAM17 is rendered incapable of helping the cancer tumor grow and it provides us with fundamental knowledge, which may be used to improve future cancer treatments.

"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 states.

Dr. Kveiborg's group is currently conducting animal experiments to learn more about the effect of ADAM17-inhibition.

"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 concludes.

[Press release] [Nature Communications abstract]