Inhibition of Protein Disulfide Isomerase (PDIA1) Leads to Proteasome-Mediated Degradation of Ubiquitin-like PHD and RING Finger Domain-Containing Protein 1 (UHRF1) and Increased Sensitivity of Glioblastoma Cells to Topoisomerase II Inhibitors.

Glioblastoma (GBM) is the most aggressive brain tumor, and the prognosis remains poor with current available treatments. PDIA1 is considered a promising therapeutic target in GBM. In this study, we demonstrate that targeting PDIA1 results in increased GBM cell death by topoisomerase II (Top-II) inhibitors resulting in proteasome-mediated degradation of the oncogenic protein UHRF1. Combination of the PDIA1 inhibitor, bepristat-2a, produces strong synergy with doxorubicin, etoposide, and mitoxantrone in GBM and other cancer cell lines. Our bioinformatics analysis of multiple datasets revealed downregulation of UHRF1 , upon PDIA1 inhibition. In addition, PDIA1 inhibition results in proteasome-mediated degradation of UHRF1 protein. Interestingly, treatment of GBM cells with bepristat-2a results in increased apoptosis and resistance to ferroptosis. Our findings emphasize the importance of PDIA1 as a therapeutic target in GBM and present a promising new therapeutic approach using Top-II inhibitors for GBM treatment.