Abstract

To maintain their growth rate, cancer cells must secure a supply of fatty acids, which are necessary for building cell membranes and maintaining energy processes. This is one of the reasons why tissues with intensive fatty acid metabolism, such as the mammary gland, are more likely to develop tumours. One natural or induced defence process against cancer is ferroptosis which interferes with normal fatty acid metabolism. This leads to the oxidation of polyunsaturated fatty acids, which causes a rearrangement of the metabolism and damages cell membranes. As a consequence of this oxidation there is a shortage of normal polyunsaturated fatty acids, which disturbs the complicated metabolism of fatty acids. This imbalance in metabolism, resulting from the deficiency of properly structured fatty acids, is called, by these authors, "acyl starvation". When cancer cells are exposed to alternating hypoxia and reoxygenation, they often develop resistance to neoadjuvant therapies. Blocking the stearoyl-CoA desaturase - fatty-acid-binding protein4 - fatty acid translocase axis appears to be a promising pathway in the treatment of breast cancer. On the one hand, the inhibition of desaturase leads to the formation of toxic phospholipid hydroperoxides in ferroptosis, while, on the other hand, the inhibition of fatty-acid-binding protein4 and translocase leads to a reduced uptake of fatty acids and disruption to the cellular transport of fatty acids resulting in intracellular acyl starvation. The disruption in the metabolism of fatty acids in cancer cells may augment the effectiveness of neoadjuvant therapy.

Significance Statement Regulation of the metabolism of FAs in cancer cells seems to be a promising therapeutic direction. Studies show that the induction of ferroptosis in cancer cells, combined with use of classic neoadjuvant therapies, effectively inhibits the proliferation of these cells. We link the process of ferroptosis with apoptosis and SCD1-FABP4-CD36 axis and propose the term ‘acyl starvation’ for the processes leading to FAs deficiency, dysregulation of FAs metabolism in cancer cells and, most importantly, the appearance of incorrect proportions FAs.