Regulation of mitochondrial dynamics in 2-methoxyestradiol-mediated osteosarcoma cell death. Magda Gorska-Ponikowska et al. (2021) Scientific Reports 1-12

Osteosarcoma (OS) is one of the most malignant tumors of childhood and adolescence. Research on mitochondrial dynamics (fusion/ ssion) and biogenesis has received much attention in last few years, as they are crucial for death of cancer cells. Speci cally, it was shown that increased expression of the cytoplasmic dynamin‐related protein 1 (Drp1) triggers mitochondrial ssion (division), which activates BAX and downstream intrinsic apoptosis, e ectively inhibiting OS growth. In the presented study, human OS cells (metastatic 143B OS cell line) were incubated with 2‐ methoxyestradiol (2‐ME) at both physiologically and pharmacologically relevant concentrations. Cell viability was determined by the MTT assay. Confocal microscopy and western blot methods were applied to examine changes in Drp1 and BAX protein levels. Mitochondrial Division Inhibitor 1, MDIVI‐1, was used in the study to further examine the role of Drp1 in 2‐ME‐mediated mechanism of action. To determine quantitative and qualitative changes in mitochondria, electron microscopy was used. 2‐ME at all used concentrations increased mitochondrial ssion and induced autophagy in OS cells. At the concentration of 1 μM 2‐ME increased the area density of mitochondria in OS cells. Subsequent, upregulated expression of Drp1 and BAX proteins by 2‐ME strongly suggests the activation of the intrinsic apoptosis pathway. We further observed 2‐ME‐mediated regulation of glycolytic state of OS cells. Therefore, we suggest that changes of mitochondrial dynamics may represent a novel mechanism of anticancer action of 2‐ME. This finding may open new approaches to improve the e cacy of chemotherapy in the treatment of OS, however, it has to be confirmed by in vivo studies.