Induction of 2-hydroxycatecholestrogens O-methylation: A missing puzzle piece in diagnostics and treatment of lung cancer
Claudia Musial,
Narcyz Knap,
Renata Zaucha,
Paulina Bastian,
Giampaolo Barone,
Giosuè Lo Bosco,
Fabrizio Lo-Celso,
Lucyna Konieczna,
Mariusz Belka,
Tomasz Bączek,
Antonella Marino Gammazza,
Alicja Kuban-Jankowska,
Francesco Cappello,
Stephan Nussberger,
Magdalena Gorska-Ponikowska
Affiliations
Claudia Musial
Department of Medical Chemistry, Medical University of Gdansk, Debinki 1, 80-211, Gdansk, Poland
Narcyz Knap
Department of Medical Chemistry, Medical University of Gdansk, Debinki 1, 80-211, Gdansk, Poland
Renata Zaucha
Department of Clinical Oncology and Radiotherapy, Medical University of Gdansk, 80-214, Gdansk, Poland
Paulina Bastian
Department of Medical Chemistry, Medical University of Gdansk, Debinki 1, 80-211, Gdansk, Poland
Giampaolo Barone
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90128, Palermo, Italy
Giosuè Lo Bosco
Department of Mathematics and Computer Science, University of Palermo, 90133, Palermo, Italy; Euro-Mediterranean Institute of Science and Technology, 90139, Palermo, Italy
Fabrizio Lo-Celso
Department of Physics and Chemistry ‘Emilio Segrè’, University of Palermo, 90128, Palermo, Italy
Lucyna Konieczna
Department of Pharmaceutical Chemistry, Medical University of Gdansk, 80-416, Gdansk, Poland
Mariusz Belka
Department of Pharmaceutical Chemistry, Medical University of Gdansk, 80-416, Gdansk, Poland
Tomasz Bączek
Department of Pharmaceutical Chemistry, Medical University of Gdansk, 80-416, Gdansk, Poland
Antonella Marino Gammazza
Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, 90127, Palermo, Italy
Alicja Kuban-Jankowska
Department of Medical Chemistry, Medical University of Gdansk, Debinki 1, 80-211, Gdansk, Poland
Francesco Cappello
Euro-Mediterranean Institute of Science and Technology, 90139, Palermo, Italy; Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, 90127, Palermo, Italy
Stephan Nussberger
Department of Biophysics, Institute of Biomaterials and Biomolecular Systems, University of Stuttgart, 70569, Stuttgart, Germany
Magdalena Gorska-Ponikowska
Department of Medical Chemistry, Medical University of Gdansk, Debinki 1, 80-211, Gdansk, Poland; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90128, Palermo, Italy; Euro-Mediterranean Institute of Science and Technology, 90139, Palermo, Italy; Department of Biophysics, Institute of Biomaterials and Biomolecular Systems, University of Stuttgart, 70569, Stuttgart, Germany; Corresponding author. Department of Medical Chemistry, Medical University of Gdansk, Debinki 1, 80-211, Gdansk, Poland.
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.
