Vitamin K prevents cell death (new function) + Cool temps inhibits cancer (in mice)

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Vitamin K prevents cell death: a new function for a long-known molecule

RELEASE: A team of researchers located at Helmholtz Munich reports on a novel function of vitamin K, which is generally known for its importance in blood clotting. The researchers discovered that the fully reduced form of vitamin K acts as an antioxidant efficiently inhibiting ferroptotic cell death. Ferroptosis is a natural form of cell death in which cellular iron plays an important role and which is characterized by the oxidative destruction of cellular membranes. In addition, the team identified FSP1 as the warfarin-insensitive enzyme reducing vitamin K, the identity of which had been postulated but remained unknown for more than half a century.

During the last years, ferroptosis has been implicated as a driver of Alzheimer's disease and acute organ injuries among many other diseases. Thus, the present findings put forward the concept that vitamin K treatment might be a new powerful strategy to ameliorate these ferroptosis-related diseases.

Vitamin K is a potent ferroptosis suppressor. Since ferroptosis prevention is considered a highly promising approach for the therapy of many degenerative diseases, new mechanisms and compounds regulating ferroptosis are extensively being explored. To identify these new molecules, a team of researchers led by Dr. Eikan Mishima and Dr. Marcus Conrad, both from the Institute of Metabolism and Cell Death at Helmholtz Munich, along with collaborators from Tohoku University (Japan), University of Ottawa (Canada) and Technical University of Dresden (Germany), systematically studied a number of naturally occurring vitamins, as well as their derivatives. "Surprisingly, we identified that vitamin K, including phylloquinone (vitamin K1) and menaquinone-4 (vitamin K2), is able to efficiently rescue cells and tissues from undergoing ferroptosis" Dr. Eikan Mishima, first author of the study explained.

Unraveling the long sought-after vitamin K reducing enzyme FSP1. In 2019 a team of researchers around Dr. Marcus Conrad already identified an enzyme as a novel and strong inhibitor of ferroptosis: ferroptosis suppressor protein-1, short FSP1. The research team now found that the fully reduced form of vitamin K (i.e., vitamin K hydroquinone) acts as a strong lipophilic antioxidant and prevents ferroptosis by trapping oxygen radicals in lipid bilayers. In addition, they identified that FSP1 is the enzyme that efficiently reduces vitamin K to vitamin K hydroquinone, thereby driving a novel non-canonical vitamin K cycle. Since vitamin K is critically involved in blood clotting processes, the team further showed that FSP1 is responsible for the vitamin K-reduction pathway insensitive against warfarin, one of the most commonly prescribed anticoagulants.

Breakthrough in understanding vitamin K metabolism. Unraveling the identity of this enzyme solved the last riddle of vitamin K metabolism in blood clotting and elucidated the molecular mechanism of why vitamin K constitutes the antidote for overdosing of warfarin. "Our results therefore link the two worlds of ferroptosis research and vitamin K biology. They will serve as the stepping stone for the development of novel therapeutic strategies for diseases where ferroptosis has been implicated," Dr. Marcus Conrad highlighted. In addition, since ferroptosis most likely constitutes one of the oldest types of cell death, the researchers hypothesize that vitamin K might be one of the most ancient types of naturally occurring antioxidants. "Thus, new aspects of the role of vitamin K throughout the evolution of life are expected to be unveiled" Dr. Marcus Conrad explained.

Cool room temperature inhibited cancer growth in mice

RELEASE: Turning down the thermostat seems to make it harder for cancer cells to grow, according to a study in mice by researchers at Karolinska Institutet in Sweden. The study, published in the journal Nature, found that chilly temperatures activate heat-producing brown fat that consumes the sugars the tumors need to thrive. Similar metabolic mechanisms were found in a cancer patient exposed to a lowered room temperature.

"We found that cold-activated brown adipose tissue competes against tumors for glucose and can help inhibit tumor growth in mice," says Professor Yihai Cao at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, and corresponding author. "Our findings suggest that cold exposure could be a promising novel approach to cancer therapy, although this needs to be validated in larger clinical studies."

The study compared tumor growth and survival rates in mice with various types of cancer, including colorectal, breast and pancreatic cancers, when exposed to cold versus warm living conditions. Mice acclimatized to temperatures of 4 degrees Celsius had significantly slower tumor growth and lived nearly twice as long compared with mice in rooms of 30 degrees Celsius.

To find out why that is, the researchers analyzed markers in the tissue to study cellular reactions and used imaging tests to examine glucose metabolism. Cancer cells typically need large amounts of glucose, or sugar, to grow.

They found that cold temperatures triggered significant glucose uptake in brown adipose tissue, also known as brown fat, a type of fat that is responsible for keep the body warm during cold conditions. At the same time, the glucose signals were barely detectable in the tumor cells.

When the researchers removed either the brown fat or a protein crucial for its metabolism called UCP1, the beneficial effect of the cold exposure was essentially wiped out and the tumors grew at a pace on par with those that were exposed to higher temperatures. Similarly, feeding tumor-bearing mice with a high sugar drink also obliterated the effect of cold temperatures and restored tumor growth.

"Interestingly, high sugar drinks seem to cancel out the effect of cold temperatures on cancer cells, suggesting that limiting glucose supply is probably one of the most important methods for tumor suppression," Yihai Cao says.

To study the human relevance of the findings, the researchers recruited six healthy volunteers and one patient with cancer undergoing chemotherapy. Using positron emission tomography (PET) scanning, the researchers identified a significant amount of brown fat activated in the neck, spine and chest area of healthy adults wearing shorts and T-shirts while being exposed to a slightly chilly room temperature of 16 degrees Celsius for up to six hours per day for two weeks.

The patient with cancer wore light clothing while spending time in rooms of 22 degrees Celsius for a week and then in rooms of 28 degrees Celsius for four days. Prior research has shown that even though there are significant individual differences, 28 degrees Celsius is generally considered a comfortable environmental temperature (the thermoneutral temperature) for most inactive humans. The imaging scans picked up increased brown fat and lowered tumor glucose uptake during the lower versus the higher temperature.

"These temperatures are considered tolerable by most people," Yihai Cao says. "We are therefore optimistic that cold therapy and activation of brown adipose tissue with other approaches such as drugs could represent another tool in the toolbox for treating cancer."

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