Upregulation of paraoxonase-2 enzyme in human osteosarcoma and its involvement in mechanisms promoting the aggressive behavior of tumor cells

Background: Osteosarcoma (OS) is the most common bone cancer, known for its aggressive nature, high chemoresistance, and strong metastatic potential responsible for poor clinical outcomes. In this context, identifying reliable biomarkers and therapeutic targets is therefore critical. This study investigates the role of paraoxonase-2 (PON2), an intracellular enzyme known for its anti-oxidative and anti-apoptotic properties. PON2 overexpression has been observed in various cancers and is implicated in tumor development and progression. Methods and results: PON2 expression was evaluated by immunohistochemistry in bone tissue samples from OS patients and control subjects. shRNA-mediated PON2 silencing was performed in U-2 OS and Saos-2 cells to assess proliferation, viability, migration, chemosensitivity, ROS production, apoptosis activation, glucose uptake, and GLUT1 expression. PON2 overexpression and N-acetylcysteine (NAC) pre-treatment in CDDP-treated U-2 OS cells were used as rescue approaches. Preliminary analyses showed markedly higher PON2 expression in OS than in control bone specimens. PON2 knockdown reduced proliferation, viability, and migration, while enhancing sensitivity to cisplatin (U-2 OS and Saos-2) and doxorubicin (U-2 OS only); these effects were reversed by PON2 upregulation. PON2 silencing also increased ROS levels and caspase expression, and impaired glucose uptake by reducing GLUT1 expression and intracellular glucose levels. Since NAC did not fully rescue these alterations, PON2 appears to sustain chemoresistance by affecting important mechanisms related to ROS detoxification, glucose metabolism, and anti-apoptotic signaling. Conclusions: Obtained data clearly illustrate the potential of PON2 as promising biomarker and molecular therapeutic target for human OS.