March 26, 2019—In a new Science paper, Brendan Manning, professor of genetics and complex diseases, and colleagues reveal how a previously understudied enzyme may help fuel the metabolism of cancer cells and contribute to the development of other diseases, including diabetes and obesity.
Q: What is the major takeaway of this study?
A: In this study, Gerta Hoxhaj, a postdoctoral fellow in my lab, identified a previously unknown mechanism by which insulin—the hormone that regulates many metabolic processes—sends a signal to activate an important metabolic enzyme called NAD kinase, or NADK. Up until now, there hasn’t been much research done on NADK, which is surprising. It is an important enzyme because it produces a key factor, or what we sometimes call a “helper molecule,” known as NADP, which is required for a type of metabolism called anabolism. Anabolism allows cells to store energy from the nutrients we eat and it helps the body grow new cells and tissues.
Broadly speaking, my lab’s research is focused on defining the biochemical lines of communication that our cells use to sense specific nutrients and appropriately metabolize them. As we age or get sick with diseases such as diabetes or cancer, these lines of communications and the messages that are sent often malfunction. In placing NADK within the insulin pathway, this study discovers an important new metabolic target of a central line of communication that has been studied for many years and that is known to malfunction in human diseases.
Q: What are the public health implications of this finding?
A: One of the most immediately evident impacts of this study is on our understanding of the metabolism of cancer cells and how it contributes to tumor growth. Cancer-causing genetic changes frequently alter the signaling pathway stimulated by insulin, resulting in erroneous signals being sent within cancer cells. A signal that mimics insulin but doesn’t turn off when it’s supposed to can change the metabolism of cancer cells in such a way that they go into a state of uncontrolled growth, which gives rise to tumors.
In our study, we showed that the pathway leading to NADK activation is locked in the on-state in various cancer cells. In turn, greater amounts of NADP, the “helper molecule,” are produced, which can help fuel the anabolic growth of cancer cells. If we can develop a drug that targets NADK, we might be able to stop this cascade of events, which could lead to new treatments for cancer. I’m optimistic that the development of drugs that inhibit NADK is both possible and likely.
Moreover, knowing that insulin and related hormones activate NADK to produce NADP could have implications for treating obesity, type 2 diabetes, and other metabolic diseases. We’re actively researching this in the lab now.
Q: You said that this enzyme has been surprisingly understudied. Do you think this study will change that?
A: Every organism on Earth possesses its own version of the NADK enzyme. However, relative to nearly every other metabolic enzyme, there have been very few studies on NADK, especially on how it’s controlled. Most of the scientific literature on the topic is on the bacterial or plant versions of NADK. Given the importance of its product, NADP, for anabolism, the scarcity of studies on human NADK is puzzling. Our findings establish NADK as a candidate drug target for cancer treatment, and the nature of this enzyme already places it into a class of readily “druggable” targets. I suspect that this will help generate significant research interest in this enzyme and its role in human health and disease.