Induction of 2-hydroxycatecholestrogens O-methylation: A missing puzzle piece in diagnostics and treatment of lung cancer

• DOI: 10.1016/j.redox.2022.102395
• Publication Date: 2022-07-08T11:43:50Z
• Authors: Claudia Musial; Narcyz Knap; Renata Zaucha; Paulina Bastian; Giampaolo Barone; Giosuè Lo Bosco; Fabrizio Lo-Celso; Lucyna Konieczna; Mariusz Belka; Tomasz Bączek; Antonella Marino ...; Alicja Kuban-Jank...; Francesco Cappello; Stephan Nussberger; Magdalena Gorska-...
• Keywords: Lung adenocarcinoma; Medicine (General); 0303 health sciences; Estrogen metabolites; QH301-705.5; Biomarker; 2-Methoxyestradiol; 3. Good health; 03 medical and health sciences; R5-920; Non-small cell lung cancer; Lung cancer; Biology (General); Research Paper

Lung cancer is one of the most common cancers worldwide, causing nearly one million deaths each year. Herein, we present the effect of 2-methoxyestradiol (2-ME), the endogenous metabolite of 17β-estradiol (E2), on non-small cell lung cancer (NSCLC) cells. 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.