Researchers have come closer to understanding the link between metabolism and the development of cancer. A researcher says that ensuring good metabolic regulation of patients with cancer may have considerable potential in treatment.
The inextricable link between cancer and metabolism in leading to severe illness and death is still not fully understood.
It is well known that people with obesity or diabetes may be more likely to develop some types of cancer, and cancer can also trigger the development of various metabolic disorders.
This was demonstrated a few years ago in a major study in Denmark: not only did people with type 2 diabetes have an increased risk of developing cancer but also people with cancer had an increased risk of developing type 2 diabetes. The study especially associated lung cancer, breast cancer and pancreatic cancer with an increased risk of developing type 2 diabetes.
A new study in Denmark now shows that the link between cancer and metabolic disorders is probably associated with the concentrations of adenosine monophosphate–activated protein kinase (AMPK), an enzyme with a key role in cellular energy balance.
“We have tried to fill some of the big gaps in knowledge about why our patients with cancer have an increased risk of developing metabolic disorders. We found that cancer more negatively affects the metabolic health of mice lacking functional muscle AMPK. This deficiency leads to reduced insulin sensitivity, impaired glucose metabolism and poorer maintenance of muscle mass, and this may influence the trajectory of cancer,” explains a researcher behind the study, Lykke Sylow, Associate Professor, Department of Nutrition, Exercise and Sports, University of Copenhagen.
The research, much of which was carried out by Steffen Raun, a Postdoctoral Fellow in Lykke Sylow’s group, has been published in the Journal of Cachexia, Sarcopenia and Muscle.
Examined AMPK in muscle biopsies
In the collaborative study with Maastricht University, the researchers examined various proteins, including AMPK, in the muscle biopsies from the thighs of people with lung cancer.
AMPK is one of the most important metabolic regulators of cells and can determine whether cells have too much or too little energy, thus being essential for maintaining insulin sensitivity.
The study showed that people with lung cancer had upregulated levels of AMPK in the muscle cells, which was immediately counterintuitive, since this otherwise indicates that they have increased insulin sensitivity.
The researchers therefore carried out a new study that removed the function of AMPK in a mouse model of lung cancer so that the mice could not upregulate AMPK.
Compared with the mice without muscle AMPK deficiency, cancer more negatively affected the mice with the AMPK deficiency resulting in reduced insulin sensitivity, impaired glucose metabolism and poorer maintenance of muscle mass.
“We interpret these results to mean that patients with cancer upregulate AMPK as a protective mechanism aimed at maintaining cellular metabolism that is otherwise under pressure because of the cancer,” says Lykke Sylow.
Activating AMPK may improve prognosis in cancer
In the next part of the study, the researchers administered a drug to mice with lung cancer to activate AMPK. This restored certain parts of metabolism otherwise put under pressure by lung cancer.
Lykke Sylow sees clinical potential in activating AMPK as part of treatment for some patients with cancer.
“Activating AMPK would probably have great potential for patients with cancer in reducing their degree of insulin resistance and metabolic dysfunction, because these are associated with increased mortality and relapse. Further, involuntary loss of muscle mass means that many people with various types of cancer cannot tolerate certain cancer treatments. Up to 30% of patients with cancer die from loss of muscle mass, and insulin resistance would probably accelerate this loss,” explains Lykke Sylow.
Clinical trials already underway
Lykke Sylow says that clinical trials are already underway in which doctors try to activate AMPK among patients with cancer but not with the aim of regulating metabolism.
Lykke Sylow would like these ongoing studies to also investigate metabolic regulation and muscle mass.
In addition, Lykke Sylow says that exercise could also potentially increase the activity of AMPK.
“We know that AMPK is one of the proteins that is highly activated by exercise, and we would like to investigate whether patients with cancer can prevent insulin resistance through exercise-activated AMPK. The good news could probably be that patients with cancer can activate AMPK through both drug treatment and exercise, and I strongly suggest that activating AMPK in the muscles of patients with cancer could help to increase insulin sensitivity and thereby hopefully reduce some of the risks associated with dysregulated metabolism and muscle loss,” adds Lykke Sylow.
Lykke Sylow also dreams of treating patients with cancer and insulin resistance with drugs that activate AMPK in the muscles, including metformin.
In the meantime, the researchers are already starting the exercise trials.