AUTHOR=Rodenas Maria Carmen , Peñas-Martínez Julia , Pardo-Sánchez Irene , Zaragoza-Huesca David , Ortega-Sabater Carmen , Peña-García Jorge , Espín Salvador , Ricote Guillermo , Montenegro Sofía , Ayala-De La Peña Francisco , Luengo-Gil Ginés , Nieto Andrés , García-Molina Francisco , Vicente Vicente , Bernardi Francesco , Lozano María Luisa , Mulero Victoriano , Pérez-Sánchez Horacio , Carmona-Bayonas Alberto , Martínez-Martínez Irene 

TITLE=Venetoclax is a potent hepsin inhibitor that reduces the metastatic and prothrombotic phenotypes of hepsin-expressing colorectal cancer cells

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=10

YEAR=2023

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2023.1182925

DOI=10.3389/fmolb.2023.1182925

ISSN=2296-889X

ABSTRACT=<p><bold>Introduction:</bold> Hepsin is a type II transmembrane serine protease and its expression has been linked to greater tumorigenicity and worse prognosis in different tumors. Recently, our group demonstrated that high hepsin levels from primary tumor were associated with a higher risk of metastasis and thrombosis in localized colorectal cancer patients. This study aims to explore the molecular role of hepsin in colorectal cancer.</p><p><bold>Methods:</bold> Hepsin levels in plasma from resected and metastatic colorectal cancer patients were analyzed by ELISA. The effect of hepsin levels on cell migration, invasion, and proliferation, as well as on the activation of crucial cancer signaling pathways, was performed <italic>in vitro</italic> using colorectal cancer cells. A thrombin generation assay determined the procoagulant function of hepsin from these cells. A virtual screening of a database containing more than 2000 FDA-approved compounds was performed to screen hepsin inhibitors, and selected compounds were tested <italic>in vitro</italic> for their ability to suppress hepsin effects in colorectal cancer cells. Xenotransplantation assays were done in zebrafish larvae to study the impact of venetoclax on invasion promoted by hepsin.</p><p><bold>Results:</bold> Our results showed higher plasma hepsin levels in metastatic patients, among which, hepsin was higher in those suffering thrombosis. Hepsin overexpression increased colorectal cancer cell invasion, Erk1/2 and STAT3 phosphorylation, and thrombin generation in plasma. In addition, we identified venetoclax as a potent hepsin inhibitor that reduced the metastatic and prothrombotic phenotypes of hepsin-expressing colorectal cancer cells. Interestingly, pretreatment with Venetoclax of cells overexpressing hepsin reduced their invasiveness <italic>in vivo</italic>.</p><p><bold>Discussion:</bold> Our results demonstrate that hepsin overexpression correlates with a more aggressive and prothrombotic tumor phenotype. Likewise, they demonstrate the antitumor role of venetoclax as a hepsin inhibitor, laying the groundwork for molecular-targeted therapy for colorectal cancer.</p>