The role of ELOVL5 and IGFBP6 genes in modulating the sensitivity of breast cancer cells to ferroptosis

Researchers from the Faculty of Biology and Biotechnology at the Higher School of Economics conducted a joint study with colleagues from National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, Center for Digital Biodesign and Personalized Health Care (Sechenov University) and Institute of Bioorganic Chemistry of the Russian Academy of Sciences, dedicated to the study of the link between low expression of the IGFBP6, ELOVL5 genes and lipid metabolism in breast cancer cells. The results of the study will be published in the journal Frontiers in Molecular Biosciences.

Breast cancer recurrence is one of the key barriers to successful cancer treatment. Previously, HSE scientists showed that low expression of the ELOVL5 and IGFBP6 genes in malignant tumor tissues of the breast is associated with a poor prognosis. Moreover, the ELOVL5 gene is directly involved in the elongation of polyunsaturated fatty acids (PUFAs), which are believed to play an important role in the metabolism of cancer cells. In this regard, in a new study, biologists focused their work on changes in lipid metabolism in breast cancer cells with reduced expression of either the ELOVL5 or IGFBP6 gene.
To do this, the study used MDA-MB-231 cells with a stable knockdown of the ELOVL5 or IGFBP6 genes. Gene expression was assessed using transcriptomic and proteomic analysis, as well as using real-time PCR. The content of individual fatty acids in the cells was measured using HPLC-MS. HPLC was used to analyze the absorption kinetics of PUFAs. Cell viability was measured by the MTS test. Flow cytometry was used to measure the apoptosis activation, fluorescence microscopy was used to assess ROS accumulation and lipid droplet formation. Glutathione peroxidase activity was measured by colorimetric assay.
As a result of this study, the scientists found that knocking down the IGFBP6 gene resulted in significant changes in the fatty acid profile in cells and in the expression of many genes associated with lipid metabolism. Some PUFAs are known to inhibit proliferation and cause cancer cell death, so the researchers also tested the response of cells to individual PUFAs and to combinations of docosahexaenoic acid (DHA, n3 PUFA) with standard chemotherapy drugs. The data obtained indicate that extrinsic PUFAs cause cell death by activating ferroptosis, an iron-dependent mechanism of cell death during excessive lipid peroxidation. Moreover, both knockdowns (ELOVL5 and IGFBP6) were found to increase the sensitivity of cells to ferroptosis, probably due to a significant decrease in the activity of the antioxidant enzyme GPX4. Also, the addition of DHA to widely used chemotherapy drugs significantly enhanced their effect, especially against cells with low expression of the IGFBP6 gene.
Thus, the results of this study showed that in breast cancer the inclusion of PUFAs in the treatment regimen for patients with low expression of the IGFBP6 and ELOVL5 genes can be potentially beneficial and deserves to be tested in a clinical setting.