Magmas Inhibition in Prostate Cancer: A Novel Target for Treatment-Resistant Disease

SIMPLE SUMMARY: Metastatic and treatment-resistant prostate cancer remains a life-threatening disease despite recent therapeutic advances. Literature suggests that treatment resistance and prostate cancer progression is associated with prostate cancer stem cells. In this study, we evaluated the role of the mitochondria-associated granulocyte–macrophage colony-stimulating factor signaling (Magmas) protein as a molecular target and applied a novel Magmas inhibitor, BT#9, on prostate cancer cells and normal control cells. We found that Magmas was overexpressed in human prostate cancers and its expression was linked to the aggressiveness of the disease. BT#9 downregulated Magmas expression, reduced viability and induced apoptotic cell death in prostate cancer cells. The mechanism of cell death by BT#9 is mainly caspase-independent and via a Reactive Oxygen Species (ROS)-mediated pathway. This is the first study that has evaluated targeting the Magmas protein in prostate cancer and, to our knowledge, the first to elucidate the potential molecular mechanism of BT#9 activity in prostate cancer, including the mode of cell death and the critical role of ROS accumulation. Our work may provide a potential clinical application for a novel prostate cancer treatment that can overcome cancer stem cell and therapeutic resistance. ABSTRACT: The purpose of our study was to evaluate Magmas as a potential target in prostate cancer. In addition, we evaluated our synthetic Magmas inhibitor (BT#9) effects on prostate cancer and examined the molecular mechanism of BT#9. A cell viability assay showed that treatment with BT#9 caused a significant decrease in the viability of DU145 and PC3 prostate cancer cells with little effect on the viability of WPMY-1 normal prostate cells. Western blot proved that BT#9 downregulated the Magmas protein and caspase-3 activation. Flow cytometry studies demonstrated increased apoptosis and disturbed mitochondrial membrane potential. However, the main mode of cell death was caspase-independent necrosis, which was correlated with the accumulation of mitochondrial and intra-cellular Reactive Oxygen Species (ROS). Taken together, our data suggest Magmas is a potential molecular target for the treatment of prostate cancer and that Magmas inhibition results in ROS-dependent and caspase-independent necrotic cell death.