Lung cancer is one of the most common cancers worldwide, causing nearly one million deaths each
year. In this manuscript, we present the effect of 2-methoxyestradiol (2-ME), the endogenous
metabolite of 17β-estradiol (E2), on non-small cell lung cancer cells (NSCLC). We observed that
2-ME reduced the viability of lung adenocarcinoma in two-dimensional (2D) and three-dimensional
(3D) spheroidal A549 cell culture models. Molecular modeling was carried out aiming to visualize
amino acid residues within binding pockets of the acyl-protein thioesterases, namely 1 (APT1) and 2
(APT2), and thus to identify which ones were more likely involved in the interaction with 2-ME. Our
findings suggest that 2-ME acts as an APT1 inhibitor enhancing protein palmitoylation and oxidative
stress phenomena in the lung cancer cell. In order to support our data, metabolomics of blood serum
from NSCLC patients was also performed. Moreover, computational analysis suggests that 2-ME as
compared to other estrogen metabolism intermediates is relatively safe in terms of its possible
non-receptor bioactivity within healthy human cells due to a very low electrophilic potential and
hence no substantial risk of spontaneous covalent modification of biologically protective
nucleophiles.
We propose that 2-ME can be used as a selective tumor biomarker in the course of certain
types of lung cancers and possibly as a therapeutic adjuvant or neoadjuvant.
For reference, see Induction of 2-hydroxycatecholestrogens O-methylation: A missing puzzle piece in diagnostics and treatment of lung cancer. Musial C., Knap N., Zaucha R., Bastian P., Barone G., Lo-Bosco G., Lo-Celso F., Konieczna L., Belka M., Baczek T., Gammazza A.M., Kuban-Jankowska A., Cappello F., Nussberger S. & Gorska-Ponikowska M. Redox Biology 55:1-13, 102395 (2022). doi.org/10.1016/j.redox.2022.102395