Ananya Dutta, Bose Institute
The contribution of several nutrients to cancer cells’ biosynthetic, bioenergetic, and antioxidant requirements has been intensively researched over the last decade. The connection between cancer genetics and metabolic rewiring, in particular, has resulted in significant findings, opening up new treatment avenues for certain cancer types. Clinicians are interested in how food affects cancer outcomes, but few clinical trials have explored how dietary variables promote cancer development. However, the re-emergence of tumor metabolism as a potential field of study for the discovery of novel anticancer therapies provides a chance to better investigate the relationship between nutrition and tumor development and optimize clinical protocol.
Several studies have found that cancer cell proliferation is strongly dependent on fatty acid (FA) absorption and oxidation in various animal tumor models. Olivier Feron and his group at Université Catholique de Louvain previously demonstrated that tumor acidosis, in particular, was linked with a dramatic rewiring of FA metabolism, with glutamine functioning as an FA precursor while absorption of exogenous FAs promoted beta-oxidation and triglyceride accumulation into lipid droplets (LDs). Furthermore, they demonstrated that these LDs serve as a source of FAs, which may be mobilized and oxidized to meet cellular requirements throughout the invasion process. In simple terms, it can be said that the greed for fatty acids proves to be deadly for cancer cells.
Recently the group published an interesting article in Cell Metabolism where it was hypothesized that acidic cancer cells’ increased FA uptake competence could account for the favored release of PUFAs into this specific tumor compartment, and thus for tumor-specific cytotoxicity. They discovered that n-3, but not surprisingly, n-6 PUFAs caused cell death in 2D-grown acid-adapted cancer cells and the acidic compartment of 3D-grown cancer tumor spheroids, with the toxicity increasing with the number of double bonds. The earlier accumulation of n-3 and n-6 PUFAs into LDs was larger than that of saturated FAs (SFAs) and monounsaturated FAs (MUFAs), suggesting that storing excess FAs in triglycerides was a strategy to protect double bonds against peroxidation.
They further demonstrated that the peroxidability potential of acidic malignant cells was enhanced and that long-chain (LC) n-3 and n-6 PUFA peroxidation and consequent ferroptosis accounted for the pragmatic anticancer effects. Finally, when compared to a MUFA-rich diet, an n-3 LC-PUFA-rich diet resulted in a substantial delay in tumor development in mice. Importantly, the anticancer effects of LC-PUFAs were enhanced in vitro and in vivo by the addition of inhibitors of diacylglycerol acyltransferases to prevent PUFA buffering into LDs. Overall, their findings point to dietary LC-PUFA as an adjuvant strategy for taking advantage of acidosis-induced ferroptosis in malignancies.
The findings portray the rewiring of lipid metabolism associated with tumor acidosis as a cancer cell vulnerability that may be exploited to increase LC-PUFA effects locally rather than as a druggable target that can be blocked. Because of the well-established relationship between tumor acidosis and ailment development, including increased invasiveness, treatment resistance, and immunological evasion, dietary n-3 LCPUFA supplementation is a very crucial approach to execute.
In conclusion, the greed for fatty acids (FAs) become lethal for Cancer.
Also read: A Viral DNA-packaging Motor Mechanism
References:
1. Vander Heiden, M. G., & DeBerardinis, R. J. (2017). Understanding the Intersections between Metabolism and Cancer Biology. Cell, 168(4), 657–669. https://doi.org/10.1016/j.cell.2016.12.039
2. Wu, J., et al., Interspecies Chimerism with Mammalian Pluripotent Stem Cells. Cell, 2017. 168(3): p. 473-486.e15.
3. Tajan, M. and K.H. Vousden, Dietary Approaches to Cancer Therapy. Cancer Cell, 2020. 37(6): p. 767-785.
4. Dierge, E., et al., Peroxidation of n-3 and n-6 polyunsaturated fatty acids in the acidic tumor environment leads to ferroptosis-mediated anticancer effects. Cell Metabolism.
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