Identified mechanism by which omega-3 fatty acids are “poison” for tumors

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What we commonly refer to as “good fatty acids” or polyunsaturated fatty acids (PUFAs) are essential to human health and are considered important as part of a healthy diet. Among these, the omega-3 (n-3) PUFA, DHA (docosahexaenoic acid), is crucial for brain function, eyesight and the regulation of inflammatory phenomena. DHA has also been linked to a reduction in cancer incidence, and a multidisciplinary team of researchers from the University of Leuven (UCLouvain) has now identified a biochemical mechanism known as ferroptosis, which allows DHA and other related fatty acids to slow metabolism and tumor development .

Their studies in mice showed that administration of a long-chain n-3 PUFA-rich diet significantly delayed tumor growth in mice compared to a monounsaturated FA-rich diet. The team, led by Olivier Feron, PhD, Professor, reported on their studies on cell metabolism (“Peroxidation of n-3 and n-6 ​​polyunsaturated fatty acids in the acidic tumor environment leads to ferroptosis-mediated anticancer effects”). “These data indicate dietary PUFAs as a selective adjuvant antitumor modality that can efficiently complement pharmacological approaches.”

Whether and how different nutrients could contribute to the biosynthetic, bioenergetic and antioxidant needs of cancer cells has been extensively investigated over the past ten years, the authors explained. Scientists are now also increasingly investigating whether diet can influence cancer progression by changing the access and utilization of nutrients by tumor cells, be it through restricted access or the supplementation of certain nutrients. Omega-3 fatty acid supplements have particularly attracted attention for their potential cancer-inhibiting effects. “The results of PUFA administration in tumor-bearing mice are indeed encouraging,” the team continued. However, they pointed out that “… clinical validation of potential benefits is still in its infancy …”. The interpretation of studies carried out to date can also be confusing, as the study protocols can use different PUFAs, in different amounts and with different routes of administration.

In 2016, Feron’s UCLouvain team, specializing in oncology, discovered that cells in an acidic microenvironment (acidosis) in tumors replace glucose with lipids as an energy source in order to multiply. Working with Cyril Corbet, PhD from UCLouvain, Feron showed in 2020 that these cells are the most aggressive and acquire the ability to leave the original tumor to create metastases. Yvan Larondelle, PhD, professor in the Faculty of Bioengineering at UCLouvain, whose team is developing improved nutritional lipid sources, suggested that Feron pool their skills in a research project led by PhD student Emeline Dierge to investigate the behavior of tumor cells in the presence of various fatty acids.

The results of the team’s studies showed that these acidotic tumor cells reacted in the opposite direction, depending on the fatty acid ingested. “We soon found that certain fatty acids stimulated the tumor cells while others killed them,” the researchers explained. And in particular, they found that DHA literally poisons these cancer cells.

For their study, the UCLouvain researchers used a 3D tumor cell culture system called spheroids. In the presence of DHA, the spheroids first grew and then imploded. “We found that n-3, but also notably n-6 PUFAs induced cell death in 2D-cultured acid-adapted cancer cells and in the acidic compartment of 3D tumor spheroids,” they wrote. Tumor-bearing mice fed a DHA-enriched diet also showed much slower tumor development than mice on a conventional diet. “… we have documented in mice that a diet rich in n-3 LC-PUFA led to a significant delay in tumor growth compared to a diet rich in MUFA.”

A team from the University of Leuven has discovered 3D tumors which, thanks to the action of a well-known omega-3 (DHA, mainly in fish), dissolve within a few days. Hungry for fatty acids, tumor cells suck on DHA when they become too acidic, but cannot store it properly and literally poison themselves. The result? They die. [Copyright UCLouvain]The team’s analyzes showed that DHA acts on tumor cells through a phenomenon called ferroptosis, a type of cell death associated with the peroxidation of certain fatty acids. The greater the amount of unsaturated fatty acids in the cell, the greater the risk of their oxidation. Normally, cells in the acidic compartment of tumors store these fatty acids in lipid droplets, a kind of bundle in which fatty acids are protected from oxidation. In the presence of a large amount of DHA, however, the tumor cell is overwhelmed and cannot store the DHA, which oxidizes and leads to cell death.

By using a lipid metabolism inhibitor that prevents the formation of lipid droplets, the researchers were able to observe that this phenomenon is further exacerbated, confirming that the identified mechanism is responsible for tumor inhibition. “Overall, these data identify dietary LC-PUFA as an adjuvant modality to leverage the acidosis-induced induction of ferroptosis in tumors,” the team concluded. “Mechanistically, we provide evidence that ferroptosis, an iron-dependent, non-apoptotic form of cell death associated with oxidized lipids, is promoted when acid cancer cells fail to buffer the increased uptake of PUFAs and expose themselves to the harmful effects of peroxidation. ”

It is important that the work also provides evidence that the need for bioactive n-3 LC-PUFAs in the tumor can be reduced by the simultaneous administration of DGAT inhibitors. “… an n-3 long-chain PUFA-rich diet significantly delayed tumor growth in mice compared to a monounsaturated FA-rich diet, an effect that was intensified by the administration of DGATi or ferroptosis inducers.”

The overall findings could open the door to new combined treatment options. “The well-established relationship between tumor acidosis and disease progression, also through increased invasiveness, drug resistance and immune defense, makes dietary supplementation with n-3 LC-PUFA a particularly relevant strategy for implementation,” suggested the authors.

For one adult they also found: “It is recommended that you consume at least 250 mg of DHA per day. However, studies show that our diet only provides 50 to 100 mg per day on average. This is well below the recommended minimum intake. “

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