Silkina Mariia, Razumovskaya Alexandra, Kulagin Timur, Fatkulin Artem, Klycheva Karina, Olkhovik Darya, Averinskaya Darya, Kolodeeva Oksana, Kolodeeva Olga, Tonevitsky Alexander, Nikulin Sergey
Faculty of Biology and Biotechnology, National Research University Higher School of Economics, Moscow, Russia.
Faculty of Biology and Biotechnology, National Research University Higher School of Economics, Moscow, Russia; P. A. Hertsen Moscow Oncology Research Center, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, Russia; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia.
Biochimie. 2025 Jul;234:48-61. doi: 10.1016/j.biochi.2025.03.010. Epub 2025 Apr 1.
Breast cancer remains a major challenge and new therapeutic approaches are needed for its treatment. Ferroptosis is considered a promising alternative cell death mechanism to eliminate resistant cancer cells. In previous works, we identified that lower IGFBP6 gene expression in tumor tissue corresponds to a worse prognosis for breast cancer patients and, at the same, time makes them more sensitive to ferroptosis. In this study, we further investigated the mechanism of ferroptosis induction in IGFBP6 knockdown and control MDA-MB-231 breast cancer cells by the canonical ferroptosis inducer erastin and omega-3 docosahexaenoic acid (DHA). Our results indicate that there is a significant overlap between the mechanisms of action of both of these molecules, as they regulate the same subset of genes, and their action can be inhibited by canonical ferroptosis inhibitors. On the other hand, we also observed significant differences between the effects of erastin and DHA. The most notable of these are the additional activation of apoptosis-related genes by DHA and its minor peroxidation of mitochondrial lipid membranes. Interestingly, our kinetic analysis of ferroptosis induction showed that IGFBP6 knockdown cells began to die earlier and could hardly be rescued from erastin-induced ferroptosis by mitochondrial antioxidant SkQ1, in contrast to control cells. Overall, our data suggest that the action of DHA is less dependent on mitochondrial membrane peroxidation during ferroptosis induction, and this molecule can be a promising candidate for the treatment of breast cancer, especially in the case of reduced IGFBP6 gene expression in cancer cells.
乳腺癌仍然是一个重大挑战，需要新的治疗方法来治疗。铁死亡被认为是一种有前景的替代性细胞死亡机制，可用于消除耐药癌细胞。在之前的研究中，我们发现肿瘤组织中较低的IGFBP6基因表达与乳腺癌患者较差的预后相对应，同时使他们对铁死亡更敏感。在本研究中，我们通过典型的铁死亡诱导剂埃拉斯汀和ω-3二十二碳六烯酸（DHA），进一步研究了IGFBP6基因敲低的和对照MDA-MB-231乳腺癌细胞中铁死亡诱导的机制。我们的结果表明，这两种分子的作用机制存在显著重叠，因为它们调节相同的基因子集，并且它们的作用可以被典型的铁死亡抑制剂抑制。另一方面，我们也观察到埃拉斯汀和DHA的作用之间存在显著差异。其中最显著的是DHA对凋亡相关基因的额外激活及其对线粒体脂质膜的轻微过氧化作用。有趣的是，我们对铁死亡诱导的动力学分析表明，与对照细胞相比，IGFBP6基因敲低的细胞更早开始死亡，并且几乎无法通过线粒体抗氧化剂SkQ1从埃拉斯汀诱导的铁死亡中挽救出来。总体而言，我们的数据表明，DHA在铁死亡诱导过程中的作用较少依赖于线粒体膜过氧化，并且该分子可能是治疗乳腺癌的一个有前景的候选药物，特别是在癌细胞中IGFBP6基因表达降低的情况下。
